The Immune System and the Kitzmiller Case

The evolution of the immune system was one of the most significant scientific subjects to the Kitzmiller v. Dover trial. Creationists and ID proponents have long argued that the immune system could not arise by natural means, and the plaintiffs took particular care to demonstrate the scientific absurdity of this claim.

Testimony and analysis related to the immune system are listed below.

Annotated Bibliography on the Evolutionary Origin of the Vertebrate Immune System

Books and articles on the evolution of the immune system. Click to enlarge.

by Nick Matzke

This webpage contains the same articles and books used during the Behe cross-examination that are listed in the Supplementary Material for Bottaro et al. (2006). Here, the citations have been placed in chronological order, and each reference is annotated with a blue box containing a short summary of the significance of the paper, and if relevant, significant quotes from the paper.

Sections:
Introduction
Why the Immune System?
Scientific Background
How the Bibliography was Assembled
The Larger Context
Major Themes
Annotated Bibliography in Chronological Order
Acknowledgements

Introduction

The purpose of this annotated bibliography is to give the nonspecialist reader some sense of the scholarly weight of the evolutionary immunology literature (here is another method). In particular, this bibliography focuses attention on the scientific work that developed, tested, and established the "transposon hypothesis" for the origin of receptor rearrangement in the adaptive immune system. Contrary to the impression one might get from the ID literature, the transposon hypothesis was not idle speculation, it was not thought up yesterday over breakfast, it is not particularly vague, it is not untestable, and it is not scientifically useless. In contrast, by reading through the bibliography in chronological order, we can see that the transposon hypothesis was explicitly proposed and published in top journals, it was carefully and seriously discussed for decades in the professional literature, it has inspired a very productive research program (both experimental and comparative), it has been tested with diverse evidence by researchers working in many different labs, and it has been dramatically confirmed.

In short, it is a classic case of serious, advancing evolutionary science. Without ever getting mentioned in a newspaper article or cable news show, hundreds of PhD scientists have devoted their careers to working out how and why the immune system evolved. Any one of these researchers has quietly produced more research results than the entirety of the intelligent design movement with their collection of op-eds, webpages, in-house publications, books published by InterVarsity Press, one or two books by slightly more rigorous publishers but with dubious peer-review, and one or two review articles slipped into obscure journals. Unlike "intelligent design" proponents, evolutionary immunologists repeatedly published their key work in top journals. For some reason, they have not felt the need to write law review articles, lobby school boards and legislatures to get their view taught, or muck around with state science standards, because they know that scientific hypotheses succeed by convincing other scientists through research.

For more along these lines, see Bottaro et al. (2006) and the

Why the Immune System?

The decision to make the evolution of the immune system a key example in both Kenneth Miller's direct testimony and Michael Behe's cross-examination was based on several factors. First, among the major systems that Behe discusses in Darwin's Black Box, such as the eukaryotic cilium, the bacterial flagellum, the blood-clotting cascade, and the immune system, Behe makes particularly florid claims about the absence of literature on the origin of the immune system -- for example:
As scientists we yearn to understand how this magnificent mechanism came to be, but the complexity of the system dooms all Darwinian explanations to frustration. (Darwin's Black Box, p. 139)
We can look high or we can look low, in books or in journals, but the result is the same. The scientific literature has no answers to the question of the origin of the immune system. (Darwin's Black Box, p. 138)
These are claims crying out for refutation. As it happens, there is probably more scientific literature directly on the evolution of the immune system than on the other three systems put together (we can chalk this up to (1) the long tradition of evolutionary and comparative studies in immunology; (2) the age of the discipline (going back to the 1800's); and (3) the massive amount of medical research money available for studies of the immune system, for obvious reasons). So, while Behe makes various mistakes on the other systems, many also discussed at trial, he is most dramatically wrong about the immune system literature.

Second, although the immune system is very complex, everyone is familiar with (a) its importance, (b) vaccinations and immunity to disease, and (c) many people have heard of antibodies. So it is actually not so difficult for a nonspecialist, such as a lawyer or judge, to realize the importance of immune system research.

Third, those in the community of "creationism watchers" knew that the ID advocates were particularly vulnerable on the immune system, given their past flailings in response to internet challenges. Some of this is mentioned in Bottaro et al. (referencing these Panda's Thumb posts: [1] -- [2]) and Michael Behe's weak response. For an earlier episode often recalled by creationism watchers see this celebrated discussion on an ID bulletin board, where several pro-evolution posters challenged several leaders of the ID movement to admit that Behe's 1996 claim was wrong.

Fourth, Behe's dismissal of several famous articles on evolutionary immunology during his deposition also increased confidence that he was not at all familiar with the literature, and instead would brush off any challenges as not meeting his requirement for infinite detail.

Fifth, plaintiffs' attorney Eric Rothschild had the strength of will to continue with the immune system gambit, despite Nick Matzke's early attempt at explaining the evolution of V(D)J recombination to him on a whiteboard:

The beginnings of the immune system "battle plan" for the Behe cross-examination. Whiteboard drawings from May 2005, NCSE office. Click to see larger images.

Scientific Background

The annotated bibliography will not make much sense without a little background understanding of immunology. If you can understand this basic terminology, you should be well on your way to understanding the transposon hypothesis:

  • Adaptive immune system (AIS): The portion of the immune system that generates receptors that specifically recognize and bind to a particular pathogen. This system has "memory", so that if a pathogen returns, it will be recognized much more quickly the second time around. Vaccines expose a person to a killed or weakened form of a pathogen, or key pieces of a pathogen. This "trains" the immune system to recognize common pathogens such as smallpox or polio, so that immunity can be developed without the person having to catch and fight off the actual disease. The adaptive immune response is restricted to jawed vertebrates (i.e., all vertebrates except lampreys and hagfish), and therefore evolved 450-500 million years ago in the common ancestor of cartilagenous fish (sharks and rays) and other "fish" (bony fish, including tetrapods). (Note: there is increasing evidence of different forms of adaptive responses in other organisms.)

  • Innate immune system: The portion of the immune system that uses general, nonspecific responses to fight pathogens. For example, a receptor molecule called TLR5 recognizes flagellin, the major component of bacteria flagella and a common conserved feature. The innate immune system is the first line of defense, and many of its features are shared between vertebrates and invertebrates

  • Immunoglobulins (Igs), also called antibodies: These are the receptor proteins of the immune system. They have a "Y" shape, where the top of the "Y" recognizes foreign molecules called antigens. The genes that encode immunoglobulins are composed of four basic kinds of segments: V (variable), D (diversity), J (joining), and C (constant). Vertebrates have hundreds of different copies of V, D, and J gene segments. Through a process called V(D)J recombination, different copies of these segments are spliced together, producing billions of different unique immunoglobulin receptors. Most of these receptors will not recognize a particular pathogen, but a few of them will, even if it is a completely novel pathogen.

  • Recombination Activating Gene (RAG): A RAG is a gene that codes for a RAG protein (the names of genes are italicized, and the corresponding proteins are not; sometimes PDF and HTML documents will be missing this formatting however). RAG proteins have the ability to recognize specific DNA sequences at two locations called Recombination Signal Sequences (RSSs), bring the pieces together, and cut the DNA at the RSS sites. DNA repair enzymes then repair the DNA and join the two segments, originally distant from each other, together. In the vertebrate immune system, two RAGs, RAG-1 and RAG-2, cooperate in this process.

  • Transposon: A transposon, or transposable genetic element, is a "jumping gene." The transposon is usually a gene that codes for a protein. This protein, in turn, recognizes certain signal sequences (sound familiar?) in the transposon DNA allowing it to snip out the transposon DNA and transplant it someplace else. There are many different types of transposons with various degrees of relationship to each other, and they are found in all groups of organisms. Mutations can "break" transposons, resulting in "fossil" transposons that are thought to usually be "junk DNA" (although it may play some non-coding, structural role in cells). About 3% of the human genome is composed of the remains of DNA transposons, and about half of the genome is made of various other kinds of copied repetitive DNA.

With that terminology in hand, we can discuss the transposon hypothesis. The transposon hypothesis is based on similarities between transposons and RAGs, and suggests that RAG-1 and RAG-2, and the RSSs, are actually descended from "free-living" transposons. The model states that in an early vertebrate, already equipped with an innate immune system, a transposon inserted into a non-rearranging receptor gene. When this receptor gene was expressed, the transposon was activated, and snipped itself out of the receptor. However, because this excision process was inexact, the resulting receptor would be variable, and therefore some copies of the receptor protein would be better able to recognize new or mutated pathogens. Natural selection would therefore spread this variant. An extended process of gene duplication and diversification would elaborate this basic system into the modern V(D)J recombination system.

The transposon hypothesis suggests a number of specific observations that would corroborate the model if found:

  • sequence similarities between V(D)J RSSs and transposon recognition sequences
  • RAGs should operate by mechanisms similar to transposase mechanisms
  • RAGs might still be able to perform the same functions that transposons perform, such as DNA excision and insertion
  • immunoglobulins should have relatives that are non-rearranging receptors
  • if RAGs are descended from transposons, then "free-living" transposon relatives of RAG might still exist "in the wild"

All of these observations have been published in the last 10 years. The crowning achievements, and the easiest successes to understand, were the identification of transposon relatives of RAG-1 in sea urchins, lancelets, and cnidarians (Kapitonov and Jurka, 2005) and a RAG1-RAG2 homolog serving a non-immune function in sea urchins (Fugmann et al. 2006).

If the above, very short, summary did not completely sink in, other resources are available. For an excellent moderate-length introduction to evolutionary immunology, please see Matt Inlay's online article, "Evolving Immunity." Pay particular attention to the graphics. Next, read our Nature Immunology essay for a brief update on the scientific progress of the transposon hypothesis.

See also these Panda's Thumb blogposts by Matt Inlay or Andrea Bottaro: "New discovery of missing link between adaptive immune system and transposons," "The Revenge of Calvin and Hobbes," and "Behe's meaningless complexity." Once you have given those sources a try, take several minutes to work through Figure 1 and Figure 2 of Lewis and Wu's (2000) commentary article, "The Old and the Restless", published in the Journal of Experimental Medicine. Figure 1 is a model of how receptor rearrangement works in modern organisms. Figure 2 is a model of how it evolved.

Another introductory survey can be found in the immunology textbook, Immunobiology: the immune system in health and disease. The 5th edition, Janeway et al. (2001), is freely available online in PubMed's textbooks collection. Chapter 4 is "The Generation of Lymphocyte Antigen Receptors" (sections 1, 2, 3, 4, 5). The Afterword to the book, "Evolution of the Immune System: Past, Present, and Future", is written by Janeway, and summarizes the state of knowledge as of 2001 on the evolution of the innate immune system and evolution of the adaptive immune response. The transposon hypothesis naturally plays a large role in the latter.

Hopefully, after you have worked through this material you can re-read the above summary and make some headway.


How the Bibliography was Assembled

This bibliography was originally developed for the Behe cross-examination in the Kitzmiller case, discussed in Bottaro et al. (2006). The annotations are based on notes that were taken while the bibliography was being assembled (in an all-night session the weekend before Behe testified, it must be said). The annotations have subsequently been revised and updated.

While assembling the exhibit, it was very important to make sure it was not vulnerable to some of the critiques that can be leveled against lists of articles that are uncomprehendingly culled from automated literature searches. When one searches online databases for publications that involve the keywords "immune system" and "evolution" -- two immense research topics -- one will get results on a wide variety of topics. These include:

  1. the evolution of disease organisms
  2. the evolution of modern populations in response to diseases
  3. the evolution of immune system cells when an organism's adaptive immune response is triggered (such as when someone is vaccinated)
  4. the use of customized antibodies for innumerable biomedical purposes
  5. the "evolution" of chemical reactions or biochemical reactions (this is a nonbiological definition of evolution, for example, the "evolution" of hydrogen gas during hydrolysis)
  6. clinical research on AIDS, allergies, etc.
  7. the evolution of the immune system within closely-related organisms -- e.g., mammals, birds, or tetrapods
  8. "deep" comparative immunology between vertebrates and invertebrates
  9. the selective forces driving immune system evolution and receptor diversity
  10. the origin of the innate immune system
  11. the origin of the adaptive immune system

Only the last four topics directly address the evolutionary origin of the immune system, although many of the other topics can have some relevance. Among these four topics, this bibliography focused mostly on topic #11, and included a smattering of work on topics #8, 9, and 10. Within topic #11, the origin of the V(D)J recombination system was emphasized, as it is widely seen as the "key" system, the most remarkable feature of adaptive immunity, and the biggest evolutionary "puzzle" according to ID advocates.

This bibliography also focused on the review literature rather than the research literature. First, the research literature is mostly opaque to nonspecialists, and the implications of findings are made much clearer in the review literature. Second, at his deposition, Michael Behe expressed the opinion that if scientists had made any progress worth talking about in evolutionary immunology, he would have expected to see it in the review literature. A few of the most famous research articles were included, but most of the articles are articles reviewing the research literature -- many of the review articles cite several hundred other articles.

This literature collection should not be considered comprehensive or complete -- it is merely a sample of the literature on the evolution of the adaptive immune system, focusing on V(D)J recombination, with a small sampling of literature on the evolution of innate immunity, MHC, large-scale comparative immunology, etc. For some idea of how much more scientific literature there is on this topic, see the longer unannotated bibliography.


The Larger Context

Matt Inlay (author of "Evolving Immunity" and coauthor of Bottaro et al. 2006) points out that Michael Behe's book Darwin's Black Box was ironically timed. In 1996, the year Darwin's Black Box was was published, research on V(D)J recombination was in the midst of a dramatic upswing:

Research progress on V(D)J recombination over the last 25 years. Results of a PubMed search on the term "V(D)J recombination", plotted as a function of time (blue dots). Numbers of articles per year are shown on the y-axis, and the years of publication on the x-axis. Publications for 2006 were projected based on Jan-Apr numbers. Major breakthroughs in the transposon model are listed in text boxes. The vertical line denotes 1996, the year Darwin's Black Box was published. The trendline was calculated via moving average with a period of 3.
Graph and caption by Matt Inlay.

Inlay has added to the graph boxes showing the chronology of the major research findings supporting the transposon model. The viewer can see that they came fast and furious after 1996, almost as if on cue.


Major Themes

The story told by this bibliography, and by Ken Miller's testimony in Kitzmiller, and by Bottaro et al. (2006), is basically of the proposal, development, testing, and confirmation of Sakano et al.'s 1979 suggestion in Nature that V(D)J recombination might have emerged when a transposon -- a piece of DNA that codes for a protein that can chop out that piece of DNA and insert it somewhere else -- inserted into the middle of a receptor gene. This hypothesis has been gathering steam for awhile, and really took off in the last ten years.

A subplot in the story is how evolution has played a key role in immunology throughout its development. Sakano et al.'s hypothesis was not born in a vacuum; it occurred in a field where comparative immunology, informed by evolutionary modeling, had been a core part of the discipline for a hundred years, going back to the work of Metchnikoff in the late 1800s.

If one reads chronologically through the bibliography, one will see the researchers themselves telling the same story, and citing the same papers that have been repeatedly cited in the various Behe immune system rebuttals. But you will also see some rather remarkable comments about Sakano et al.'s hypothesis. Some of the best ones will be highlighted.

For example, as the transposon hypothesis began to pick up steam in the mid-1990's, it did attract some critisms. E.g., Lewis and Wu (1997) wrote,
It is nonetheless worth noting that in spite of various similarities, there are fundamental differences between transposition and V(D)J recombination. For one, there are no reports of a transposase (mutant or otherwise) that is able to mediate site-specific inversion. Conversely, it has never been demonstrated that V(D)J recombination can cause the integration of one piece of DNA into another. (Lewis and Wu 1997, p. 162)
However, the very next year, two labs discovered that the RAG proteins actually could cause the integration reaction. In a research article in Nature entitled "Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system", Agrawal et al. write in their abstract,
Here we show that RAG1 and RAG2 together form a transposase capable of excising a piece of DNA containing recombination signals from a donor site and inserting it into a target DNA molecule. [...] The results support the theory that RAG1 and RAG2 were once components of a transposable element, and that the split nature of immunoglobulin and T-cell-receptor genes derives from germline insertion of this element into an ancestral receptor gene soon after the evolutionary divergence of jawed and jawless vertebrates.
In a commentary article in the same issue of Nature, Plasterk (1998) said, "the authors show that the RAG1 and RAG2 proteins (which mediate V(D)J joining) can still catalyse a full transposition reaction. A similar result has been independently obtained by Martin Gellert and co-workers, and is reported in tomorrow's issue of Cell." This second article was Hiom et al. (1998). In 1999, Schatz reviewed the progress of Sakano et al.'s transposon hypothesis and pronounced it a "prophetic hypothesis":
When examined in their germline configuration, the RSSs flanking V and J constitute an inverted repeat, much like that found at the end of transposons, and this realization led to the prophetic hypothesis, in 1979, that insertion of a transposable element into an ancient receptor gene exon was responsible for the generation of split antigen receptor genes during evolution ([Sakano et al., 1979]). (Schatz 1999, p. 170, bold added)
Also in 1999, Susanna Lewis -- the same Lewis as Lewis and Wu (1997) -- engaged in a little prophesy of her own. If the RAGs evolved from transposons, she said, it would be really handy to find one:
It would be extremely useful if a contemporary version of the original RAG transposon could be identified. A distant cousin, with credentials, would greatly facilitate any attempts to reconstruct the lost history between the time the first RAG element took up residence in the vertebrate genome and the emergence of a developmental recombination system. (Lewis 1999, p. 65)
Six years later, exactly this was reported by Kapitonov and Jurka (2005). It is worth pointing out that, apart from the transposon hypothesis, there was no reason whatsoever to suspect that transposons similar to RAG should exist.

Annotated Bibliography in Chronological Order

Burnet, F. M. (1971). "Self-recognition in colonial marine forms and flowering plants in relation to the evolution of immunity." Nature 232(5308): 230-235. (PubMed | DOI | Journal | Google Scholar)

The author of this article, Sir Frank MacFarlane Burnet, won the 1960 Nobel Prize in Medicine for the discovery of acquired immunological tolerance (http://nobelprize.org/medicine/laureates/1960/). He shared the award with Peter Medawar. Burnet wrote widely on the origin and evolution of the adaptive immune system in the 1960's and 1970's. Although he wrote before the molecular mechanism of recombination was understood he made many perceptive suggestions and is still commonly cited.

The 1971 Nature article is an early example of using comparative immunology in the explicit context of proposing and testing evolutionary hypotheses for the origin of the adaptive immune system. Burnet's specific point is that the ability to distinguish self from non-self is useful not just for fending off disease, but also for other purposes, e.g. detecting abnormal cancer cells, battling competing colonies in colonial tunicates, and preventing self-fertilization in flowering plants. The molecular mechanisms of recognition, such as complementary protein receptors on the cell surface, are not particularly difficult to understand. He argues that a basic self/nonself-recognition system could have provided a starting point for the evolution of the much more complex system of receptors used in the vertebrate adaptive immune system.

Burnet (1971) is cited repeatedly in the literature as outlining the subsequent research program on the origin of adaptive immunity. An example of one of Burnet's forward-looking statements:
"Much more extensive comparative studies are called for and in due course analysis of the results should allow a clear evolutionary history to emerge. Whatever form that history eventually takes we can be certain that gene duplication (gene expansion) plays a major part, and that progressive specialization of cell function and phenotypic restriction will be as conspicuous as it is in all other organs and functions." (p. 232)
Citation of Burnet (1971) is sometimes accompanied by the following quote, "Comparative studies which are not made meaningful by use of evolutionary hypotheses are bound to be sterile." This is misattributed to the 1971 article; instead, it is actually the last sentence in a 1973 Nature article by Burnet ("Multiple Polymorphism in Relation to Histocompatibility Antigens," Nature 245(5425), pp. 359-361).

Marchalonis, J. J. (1976). Immunity in Evolution. Cambridge, Mass., Harvard University Press. (Library | Amazon | Google Print)

Early synthesis of knowledge on the evolution of the immune system, published in 1976. The forward, by Frank MacFarlane Burnet, suggests that the book might emerge as "the first definitive statement of the evolutionary origins and development of vertebrate immunity" (p. xx). The author, John Marchalonis, went on to be one of the leaders in the field of immune system evolution (see his articles in this bibliography through 2006).

Chapter 1 briefly reviews the history of evolutionary immunology, which goes back to at least to Metchnikoff in late 1800's. One of the major points that emerges from comparative immunology is that the defining features of mammalian immunity are shared to different degrees with relatives on the phylogenetic tree.

In the conclusion (p. 263), Marchalonis states, "many puzzling developments in human and mammalian immunity are clarified when analyzed in an evolutionary context." His final sentence makes the point that the study of evolution has practical benefit: "The study of the phylogeny of immunity still retains the excitement of new discoveries and contributes directly toward the applied questions of immunology."

Sakano, H., Hüppi, K., Heinrich, G. and Tonegawa, S. (1979). "Sequences at the somatic recombination sites of immunoglobulin light-chain genes." Nature 280(6): 288-294. (PubMed | DOI | Journal | Google Scholar)

Famous article (within the field) that proposed the transposon hypothesis for the origin of the V(D)J recombination system of adaptive immunity. This speculation was based upon the paper's report on the role that RSSs play in the mechanism of V(D)J recombination, a discovery fundamental to modern scientific understanding of the rearrangement mechanism.
"Evolution of light-chain genes

Thus, the V-J joining may well be a reversal of an ancient accidental insertion of an IS-like [IS = insertion sequence] DNA element...."

"Fig. 6 A hypothetical scheme for the evolution of the K-light-chain genes." (p. 294)
As of summer 2005, Sakano et al. (1979) had received an extraordinary 735 citations in the scientific literature, according to the Science Citation Index.

Manning, M. J., ed. (1980). Phylogeny of Immunological Memory. Developments in Immunology. Amsterdam, Elsevier/North-Holland Biomedical Press. (Library | Amazon | Google Print)

Thirty-one chapters by various authors on comparative immunology; Proceedings of the International Symposium on Immunological Memory held at the American Society of Zoologists Meeting in Tampa, Florida, USA, 28-30 December, 1979.

Klein, J. (1986). "Evolution of Mhc." Natural History of the Major Histocompatibility Complex. New York, John Wiley & Sons: 715-762. (Library | Google Print)

This textbook provides an overview of the Major Histocompatibility Complex (MHC), a system of proteins that help distinguish self from non-self. The final chapter, chapter 10, is entitled "Evolution" and gives a review of self-recognition in various animals.

The chapter begins (p. 716):
"I believe it was Dobzhansky who said that in biology nothing makes sense except in the light of evolution. This dictum will undoubtedly apply also to the Mhc. I doubt very much if we will ever fully understand the true function of the Mhc (what purpose does the Mhc serve?), the presence of the class Ib genes in the Mhc region (why do they persist?), or the origin and purpose of the Mhc polymorphism, without exploring the source from which the Mhc sprang.

I have used the future tense in this last sentence because the study of Mhc evolution has hardly begun. Although more and more papers are being published in which the authors use the term evolution to explain this or that observation, it is significant that at the time of writing this book no paper has been published in which the Mhc DNA of a nonmammalian species has been cloned. The following pages can testify how little we know about Mhc evolution. Most of the harvesters in molecular biology have moved on to reap the next field that has ripened and have no time to finish harvesting where they began. For this reason, progress will probably be slow, particularly in these times of profit-making science. The study of evolution makes no promises as far as eliminating cancer or even producing vaccine against AIDS is concerned, and it is not easy to justify in a grant application. True, one can still make headlines by cloning bits of DNA from some extinct animal, but this probably will not last very long. Sooner or later somebody will want to know what the cloning tells us about the animals, or even whether this information is worth knowing in the first place.

The study of Mhc evolution will probably be a slow process, which will not be marked out by spectacular successess. Yet, if we want to comprehend the Mhc, we must conquer this last frontier." (p. 716)
Despite the conservative tone of this introduction, the technical discussion of MHC evolution continues for 45 pages.

Kelsoe, G. and Schulze, D. H., eds. (1987). Evolution and Vertebrate Immunity: The Antigen-Receptor and MHC Gene Families. Austin, University of Texas Press. (Library | Amazon | Google Print)

Twenty-six articles on the evolution of the immune system (71 authors). Very technical.

Síma, P. and Vetvicka, V. (1990). Evolution of Immune Reactions. Boca Raton, CRC Press. (Library | Amazon | Google Print)

Sima & Vetvicka (Preface, p. iv), begin by saying, "The purpose of this book is to reconstruct the history and evolutionary pathways of immunity among the various forms of life." (p. iv) This book is a survey of the field and all the relevant lineages. It is quite technical although the introduction and conclusion are more accessible.
"We presume that, in the next few years, the fields of comparative and evolutionary immunology will provide, not only inspiration for further investigations in biomedicine, but also a number of practical applicable results." (p. vii)

"[I]f comparative immunology is to become an exact science, it must respect the laws and knowledge not only of experimental immunology, but also those of the evolutionary sciences." (p. vii)

"From among the vertebrate taxa, we have selected only the first three classes, the Agnatha, Chondrichthyes, and Ostichthyes, in order to show where and how the morpho-functional basis of the truly adaptive immunity of the endothermic tetrapods gradually evolved." (p. v)

"In spite of the relative youthfulness of comparative immunology as a new vigorous branch of modern immunology, an impressive amount of data in this field has been amassed in many laboratories all over the world. However, our knowledge of the history of immunity is still limited. A precise understanding of how the key steps in immune evolution were achieved needs further sophisticated study and comparative research work. Many gaps still need to be filled in. Nevertheless the overall picture of the evolution of the defense system in the animal kingdom, including that of immunity, is now sufficiently well known to provide an integral overview." (p. 229)

"Evolutionary immunology is by now a continually expanding discipline that promises to provide, in the nearest future, not only new fruitful ideas and new knowledge which will be fully utilized in practice, but also a clue to the principles controlling the defense mechanisms." (p. 230)

Warr, G. W. and Cohen, N., eds. (1991). Phylogenesis of Immune Functions. Boca Raton, CRC Press. (Library | Amazon | Google Print)

Another technical work dealing with immune systems of both vertebrates and invertebrates. The introduction (p. iii) begins by citing Metchnikoff (1882). Page iii continues:
"[I]t can be argued that for a biologist to ignore the evolutionary history either of an organism or a complex system is as much an impediment to comprehending fully that organism or system as it is for a student of society to ignore the history of mankind." (p. iii)

"[W]e have concentrated on areas in which we believe that recent exciting developments have led to new insights and understanding of immunity and its evolution in diverse species." (p. iii)
In chapter 9, "Evolutionary Origins of Immunoglobulin Genes," (pp. 171-189), Litman et al. write:
"While the progressive phylogenetic development of immunoglobulin complexity is well documented, until recently little structural information at either the protein or the gene levels has been available with which to evaluate the mechanisms of evolution involved." (p. 173)
In chapter 14, "Mechanisms of Molecular Evolution in the Immunoglobulin Superfamily," (pp. 295-316), Warr & Dover write:
"Duplications, or much higher order multiplications, are obvious in the Ig family" (p. 305).
Figure 4 of this article gives a "Hypothetical scheme for the evolution of Ig genes" (p. 304). The model is pre-transposon hypothesis.

Dreyfus, D. H. (1992). "Evidence suggesting an evolutionary relationship between transposable elements and immune system recombination sequences." Molecular Immunology 29(6): 807-810. (PubMed | DOI | Journal | Google Scholar)

This paper reports sequence similarities between V(D)J recombination signal sequences, and the termini of Tcl-like transposable sequences found in invertebrates. The authors note that this supports Sakano et al.'s 1979 hypothesis:
"Sakano et al. (1979) have previously proposed that the vertebrate somatic recombination pathway evolved via the insertion of a transposable element into an ancestral gene encoding an antigen binding molecule, thus accounting for the simultaneous appearance of separated gene segments and a recombination mechanism for their reassembly." (p. 807)

"These similarities suggest that the Tcl transposition pathway may share common sequence-specific binding factors with the immunoglobulin somatic recombination pathway." (p. 807)

Síma, P. and Vetvicka, V. (1992). "Evolution of Immune Accessory Functions." Immune System Accessory Cells. Edited by L. Fornusek and P. Síma. Boca Raton, CRC Press: 1-55. (Library | Amazon | Google Print)

Long review of immune system cells across vertebrates and invertebrates. Cites Metchnikoff (1892) on p. 5. Figure 2 (p. 37) depicts the progressive emergence of various aspects of the immune system in the phylogeny of animals.
"The aim of this overview is to attempt to compare the evolutionary emergence of accessory cellular function and the role of various defense cell types in defense reactions in major natural assemblages of metazoan species." (p. 2)
The article begins with a quote from Burnet (1973) in Nature: "Comparative studies which are not made meaningful by use of evolutionary hypotheses are bound to be sterile."

Bartl, S., Baltimore, D. and Weissman, I. L. (1994). "Molecular evolution of the vertebrate immune system." Proceedings of the National Academy of Sciences 91(23): 10769-10770. (PubMed | Journal | JSTOR | Google Scholar)

This is a short (2 pages) review article. In his 1996 book Darwin's Black Box, Behe critiqued it for vagueness, but even in 1996 there were longer review articles available (e.g. Thompson 1995), and despite the shortness, the basic ideas proposed in this article and elsewhere have been dramatically confirmed in the subsequent decade, as detailed in our 2006 Nature Immunology essay.

The last sentences of Bartl et al. (1994):
"It is possible that the ancestors of RAG genes may have been horizontally transferred into a metazoan lineage at some relatively recent point in evolution. The newly introduced RAG genes may have acted, most likely with other proteins, on preexisting recombination signals (which consists of conserved heptamer and nonamer sequences) that may have been present for some other function or by random chance. In that view, the signal sequences captured the ancestors of present day TCR and immunoglobulin gene segments. Such a scenario is highly speculative but if true would imply a startling role for horizontal information transfer as the pivotal event in the evolution of vertebrate immunity." (p. 10770)

Beck, G., Cooper, E. L., Habicht, G. S. and Marchalonis, J. J., eds. (1994). Primordial Immunity: Foundations for the Vertebrate Immune System. New York, The New York Academy of Sciences. (Library | PubMed | Publisher | Amazon | Google Print)

This volume on comparative and evolutionary immunology resulted from a May 3-5, 1993 conference held in Woods Hole entitled "Primordial Immunity: Foundations for the Vertebrate Immune System." It contains 24 articles and 18 poster summaries, mostly examining the immune systems of various phylogenetically basal organisms. Three of the articles focusing on the origin of adaptive immunity are included in the articles list.

In the Preface to Primordial Immunity, editor Gail Habicht writes,
"We know -- but we need to be convincing to others -- that studies of primordial immunity have tremendous importance:
for the clues they give us to higher systems;

for their unique strategies -- some of which may be exploitable for human benefit -- not just in medicine but in agriculture where biological pest control is a desirable alternative to toxic pesticides;

but, most importantly, for their own sake.
The value of maintaining the biodiversity of our planet should be obvious: The gene pool possessed by even the lowliest creatures has the potential for enormous benefit to mankind." (p. xi, emphasis added)

Hoffman, J. A., Janeway, C. A. and Natori, S., eds. (1994). Phylogenetic Perspectives in Immunity: The Insect Host Defense. Austin, R. G. Landes Company. (Library | Amazon | Google Print)

Fifteen chapters on the immune systems of basal vertebrates and arthropods in an evolutionary perspective. Three of the most relevant chapters are:

Chapter 6, by Iwanga et al., "Clotting Cascade in the Immune Response of Horseshoe Crab" (pp. 79-96).

Chapter 11, by Eric H. Davidson, "Stepwise Evolution of Major Functional Systems in Vertebrates, Including the Immune System" (pp. 133-142).

Chapter 12, by Alister Dodds, "Molecular and Phylogenetic Aspects of the Complement System" (pp. 143-155).

Marchalonis, J. J. and Schluter, S. F. (1994). "Development of an Immune System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 1-11. (Library | PubMed | Publisher | Google Print)

Overview of the distribution and origin of major pieces of the immune system, and some discussion of the selective pressures that may have been in play. The lead author, Marchalonis, has been working on the evolutionary origin of the immune system since the 1970's.

The introductory paragraph highlights some of the practical benefits of understanding the evolution of the immune system.
"There has always been considerable interest in understanding the evolutionary origins of the immune system,1-6 and this quest has recently been given impetus by the application of advanced methods in recombinant DNA technology7-14 and immunochemistry.15-18 An understanding of the genetic mechanisms underlying the capacity of vertebrates to respond to a potentially enormous (greater than 107) set of antigenic markers associated with pathogens or cancers that might never have been presented to the animal during its evolutionary development is of general theoretical importance for the understanding of anticipatory mechanisms19 and of practical value in modulating the immune response in autoimmunity or amplifying it in cases of immunodeficiency."
The article is one of three from the special ANYAS volume Primordial Immunity which were included in the bibliography as particularly relevant to the origin of adaptive immunity. The volume contains dozens of other papers, however, so it is included in the books list as well.

Marchalonis, J. J., Hohman, V. S., Kaymaz, H., Schluter, S. F. and Edmundson, A. B. (1994). "Cell Surface Recognition and the Immunoglobulin Superfamily." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 20-33. (Library | PubMed | Publisher | Google Print)

Review of the origin and dramatic diversification of the various immunoglobulins (Igs).
"Data obtained recently on gene sequences of Igs of sharks, the ancestors of which diverged from those of mammals more than 400 million years ago, allow us to make detailed comparisons regarding the homologies among Ig V and C domains in evolution." (p. 21)

"We will analyze putative evolutionary relationships among canonical Igs and members of the Ig superfamily using highly conserved sequences from light and heavy chains of primitive vertebrates (e.g., the sandbar shark) as prototypes to ascertain similarities between Ig-related molecules of vertebrates and invertebrates." (p. 32)

Ohno, S. (1994). "MHC Evolution and Development of a Recognition System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 13-19. (Library | PubMed | Publisher | Google Print)

Argues for a relatively late origin of MHC (self-recognition capability), after the origin of adaptive immunity. This bucks the dominant view and the article explicitly takes a "devil's advocate" approach.

Stewart, J. (1994). The Primordial VRM System and the Evolution of Vertebrate Immunity. Austin, R. G. Landes. (Library | Amazon | Google Print)

This book is on the origin of the VRM system (VRM = Variable Region Molecules, see p. 9).

The evolutionary origin of various non-VRM immunity is covered on pp. 10-14 as background.
"[T]he early history of immunology was marked by an outstanding contribution which is a fine model of the methodology capable of rendering an evolutionary approach fruitful. The Russian Metchnikoff was exceptional, not only among the immunologists of his day but (unfortunately) among those of succeeding generations as well, in that his background was neither that of a chemist nor of a medical clinician, but truly that of a theoretically informed biologist." (p. 10)
The book emphasizes duplication and exaptation (e.g., see exaptation reference on p. 10: "redeployment" of single-cell feeding ability ("phagocytosis") to immune system function in multicellular animals), but it does not discuss the transposon hypothesis, even though page 45 seems to be crying out for it. However, the hypothesis only seems to have begun a resurgence in about 1994.

Stewart (1994) is cited by Behe on p. 282, note 7. Stewart is also the author of: Stewart, J. (1992) Immunoglobulins did not arise in evolution to fight infection. Immunology Today 13, 396-399.

Vetvicka, V., Síma, P., Cooper, E. L., Bilej, M. and Roch, P. (1994). Immunology of Annelids. Boca Raton, CRC Press. (Library | Amazon | Google Print)

Ten chapters on the immunology of annelids (earthworms and relatives). This may seem obscure, but the importance of annelids to evolutionary immunology is explained in Chapter 1, "Comparative Immunology: The Value of Annelids."
"[A]ll invertebrates, including annelids, have figured prominently in establishing the field of immunology." (p. 6)

"As long as there are invertebrates like earthworms, oysters, or honey bees to be protected, and others like tapeworms, slugs, and mosquitoes to be destroyed, there will be a utilitarian justification for studying invertebrate paleontology and whatever is equivalent in them to what we study in vertebrates as immunology.... Most contributors are interested mainly in what, if any, light such studies of invertebrates can throw on the evolution of the processes of inflammation and immunity as we see them in humans and the experimental mammals of the laboratory. Since Darwin, much of the 'fun' of biological research has been to interpret what directly interests one in evolutionary terms." (pp. 5-6, quoting Burnet 1971 in Nature)

Thompson, C. B. (1995). "New insights into V(D)J recombination and its role in the evolution of the immune system." Immunity 3(5): 531-539. (PubMed | DOI | Journal | Google Scholar)

A long review article summarizing the early results supporting the transposon model for the origin of adaptive immunity.
"Current evidence suggests that the ability to mount an antigen-specific immune response arose over a relatively short period of time coincident with the development of the first jawed vertebrates. This has raised the question of how a mechanism as complex as V(D)J recombination arose over such a short evolutionary period. Recent advances in V(D)J recombination suggest a resolution to this issue and allow us to reexamine the role of antigen specificity in shaping the evolution of the immune system." (p. 531)

"These observations are already renewing speculation concerning the origins of RAG1 and RAG2." (p. 532).

"Conclusion

Recent advances in our understanding of V(D)J recombination and the distribution of immunoglobulin and TCR genes in vertebrate evolution give support to the hypothesis that the V(D)J recombination arose abruptly during early vertebrate evolution. Current evidence suggests that V(D)J recombination is directed by elements that could have been derived from a transposon. [...] Colonization of the genome of an ancestral vertebrate by a transposon represents a fundamental failure of the defense systems of the organism. It is ironic that the participation of such an element in the evolution of antigen-specific immunity may have played an important role in the evolutionary success of vertebrates." (p. 538)

Bernstein, R. M., Schluter, S. F., Bernstein, H. and Marchalonis, J. J. (1996). "Primordial emergence of the recombination activating gene 1 (RAG1): Sequence of the complete shark gene indicates homology to microbial integrases." Proceedings of the National Academy of Sciences 93(18): 9454-9459. (PubMed | Journal | JSTOR | Google Scholar)

This study compared RAG1 and RAG2 in sharks and mammals, delineating the highly conserved regions. These conserved regions were found to exhibit homology to bacterial recombinases.
"Homology domains identified within shark RAG I prompted sequence comparison analyses that suggested similarity of the RAG I and II genes, respectively, to the integrase family genes and integration host factor genes of the bacterial site-specific recombination system. Thus, the apparent explosive evolution (or "big bang") of the ancestral immune system may have been initiated by a transfer of microbial site-specific recombinases." (p. 9454)
Figure 5 contains a general phylogenetic tree of the prokaryotic relatives of RAG1, and depicts the hypothesized horizontal transfer event.

van Gent, D. C., Mizuuchi, K. and Gellert, M. (1996). "Similarities between initiation of V(D)J recombination and retroviral integration." Science 271(5255): 1592-1594. (PubMed | Journal | JSTOR | Google Scholar)

This study reports close similarities between the mechanism of the formation of DNA hairpins during the cutting and assembly of antibody genes, and the processes that occur when transposons and retroviruses insert into DNA.
"These findings provide support for the speculation that the antigen receptor genes, and the RAG1 and RAG2 proteins that mediate their rearrangement, may have evolved from an ancestral transposon (18). The presence of RSSs facing in opposite directions (the most usual arrangement in the antigen receptor loci) is similar to the inverted repeat architecture of many transposon ends, and the RAG proteins could have developed from genes encoded by the former transposon."
Ref. 18 is Thompson (1995).

Hughes, A. L. and Yeager, M. (1997). "Molecular evolution of the vertebrate immune system." BioEssays 19(9): 777-786. (PubMed | Google Scholar)

Review of the evolution of several key pieces of the immune system (e.g., C3 and the other complement proteins, MHC, RAG & immunoglobulins, etc.), with a focus on the evolutionary mechanisms involved, e.g. various forms of gene duplication vs. block duplication.

Several of the key questions asked here in 1997 have been answered. The discussion of the origin of RAGs is quoted to show what was known then, and what research questions were being asked.
"Some major unanswered questions

(1) The origin of the immunoglobulin superfamily C1 type of domain

[...]

(2) Block duplication vs. functional gene clustering

[...]

(3) Conserved proteins involved in vertebrate adaptive immunity

One of the unique features of the vertebrate immune system is the rearrangement of gene segments to produce expressed Ig and TCR genes. Because these gene segments are short and have evolved rapidly, it may be very difficult to reconstruct their early evolutionary history. It may be possible, however, to obtain clues regarding the early history of Ig and TCR by studying the phylogeny of conserved proteins playing key roles in the process of rearrangement. These include the products of two genes called RAG-1 and RAG-2, which are linked in mammals. Homologues of RAG-1 have been sequenced from mammals, amphibians, bony fishes and shark(63). The RAG-1 protein shows some evidence of homology to the bacterial site-specific recombinases Fim B and Fim E(63), while RAG-2 shows homology to the bacterial recombinases Hin A(63). A phylogenetic analysis (Fig. 5), based on the region of homology between RAG-1, FimB and Fim E, illustrates this relationship. RAG-1 shows homology to eukaryotic proteins involved in such processes as excision repair (yeast RAG16(64) and regulation of gene expression (mouse rpt-1r(65) and to a human acid finger protein (66)). Interestingly, in the phylogenetic tree, RAG-1 clusters closer to the bacterial proteins than it does to any of these eukaryotic proteins (Fig. 5).

The homologies between RAG-1 and RAG-2 and bacterial proteins led Bernstein et al.(63) to suggest that somatic recombination arose in vertebrates as a result of horizontal transfer of a mictobial [sic] recombinase gene. The mere fact of homology between RAG-1 and RAG-2 and bacterial genes, however, is not evidence of horizontal gene transfer, since many vertebrate genes have prokaryotic homologues. [...] Nonetheless, Bernstein et al.(63) are correct in pointing out the potential importance of understanding the origin of this gene, and others involved in the recombination process, for gaining insights into the origin of adaptive immunity." (p. 785)
The cited references in this passage include the familiar Bernstein et al. (1996):
[References]

63 Bernstein, R., Schluter, S.F., Bernstein, H. and Marchalonis, J.J. (1996). Primordial emergence of the recombination activating gene 1 (RAG1): sequence of the complete shark gene indicates homology to microbial integrases. Proc. Natl. Acad. Sci. USA 93, 9454-9459.

64 Bang, D.d., Verhage, R., Goosen, N., Brouwer, J. and van de Putte, P. (1992). Molecular cloning of RAD16, a gene involved in differential repair in Saccharomyces cerevisiae. Nucleic Acids Res. 20, 3924-3931.

65 Patarca, R. et al. (1988). rpt-1, an intracellular protein from helper/inducer T cells that regulates gene express of interleukin 2 receptor and human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA 85, 2733-2737.

66 Chu, T.W., Capossela, A., Coleman, R., Goel, V.L., Nallur, G. and Gruen, J.R. (1995). Cloning of a new 'finger' protein gene (ZNF173) within the class I region of the human MHC. Genomics 29, 229-239.

67 Hughes, A.L. (1994). Evolution of the ATP-binding cassette transmembrane transporters of vertebrates. Mol. Biol. Evol. 11, 899-910.

Ji, X., Azumi, K., Sasaki, M. and Nonaka, M. (1997). "Ancient origin of the complement lectin pathway revealed by molecular cloning of mannan binding protein-associated serine protease from a urochordate, the Japanese ascidian, Halocynthia roretzi." Proceedings of the National Academy of Sciences 94(12): 6340-6345. (PubMed | Journal | Google Scholar)

Research paper reporting that key innate immune system genes have been discovered in tunicates, invertebrates related to vertebrates (also known as ascidians or sea-squirts).
"The major developments of the complement system, therefore, seem to have occurred in two stages; first, with the emergence in cyclostomes of the alternative pathway to establish a means of amplification, and second, after the divergence of cyclostomes but before the divergence of cartilaginous fish, the emergence of the classical and lytic pathways. This hypothesis would not only explain the evolution of the complement system, but also may help to reevaluate the activation mechanism of the mammalian alternative pathway." (pp. 6344-6345)

Lewis, S. M. and Wu, G. E. (1997). "The origins of V(D)J recombination." Cell 88(2): 159-162. (PubMed | DOI | Journal | Google Scholar)

Lewis and Wu have authored several reviews on the evolutionary origin of the adaptive immune system. This 1997 review in Cell summarizes the state of the question after several then-recent discoveries. The introductory section, "The Origins of V(D)J Recombination," discusses why the evolutionary question was attracting renewed interest:
"Recently V(D)J recombination has been partially reconstituted in vitro (reviewed in Gellert, 1996), and as a result, has been the subject of intense research. A side effect of these efforts has been renewed speculation regarding evolutionary origins. New information bears upon the possibility that this unusual recombination system could have been a transplant from the procaryotic world (Difilippantonio et al., 1996; Spanopoulou et al., 1996, van Gent et al., 1996a)." (p. 159)
This article reviews "The Case for a Transposon Progenitor" of RAG (section heading, p. 161), e.g.:
"Given that the architecture of a joining signal is transposon-like, this similarity between chemical mechanisms would seem to add weight to the idea that the V(D)J recombination system originally carried out transpositional rearrangements. The transposon theory has in fact been suggested, for various reasons, a number of times over the years." (p. 162)
On the other hand, several similarities were missing in 1997:
"It is nonetheless worth noting that in spite of various similarities, there are fundamental differences between transposition and V(D)J recombination. For one, there are no reports of a transposase (mutant or otherwise) that is able to mediate site-specific inversion. Conversely, it has never been demonstrated that V(D)J recombination can cause the integration of one piece of DNA into another." (p. 162)
Both of these features were soon discovered in lab experiments in following years.
[References]

Difilippantonio, M.J., McMahan, C.J., Eastman, Q.M., Spanopoulou, E., and Schatz, D.G. (1996). Cell 87, 253-262.

Gellert, M. (1996). Genes to Cells 1, 269-276.

Lewis, S.M. (1994). Adv. Immunol. 56, 27-150.

Spanopoulou E., Zaitseva, F., Wang, F.-H., Santagata, S., Baltimore, D., and Panaoytou, G. (1996). Cell 87, 263-276.

van Gent, D.C., Mizuuchi, D., and Gellert, M. (1996a). Science 271, 1592-1594.

van Gent, D.C., Ramsden, D.A., and Gellert, M. (1996b). Cell 85, 107-113.

Schluter, S. F., Bernstein, R. M. and Marchalonis, J. J. (1997). "Molecular origins and evolution of immunoglobulin heavy-chain genes of jawed vertebrates." Immunology Today 18(11): 543-549. (PubMed | DOI | Journal | Google Scholar)

A review of the origins of rearranging immunoglobulins in the light of cartilagenous fish, the most basal vertebrate group possessing classic adaptive immunity. The introduction clearly states the kinds of questions that an evolutionary model must answer.
"A model for the evolution of the immunoglobulins (Igs) must explain two separate but closely related aspects. The first is the genetic mechanisms by which the diversity of the expressed effector molecules is generated1. This would encompass both the enzymatic mechanism of recombination and the genomic organization of the various elements of the Ig genes. The second is the functional duality of the receptor proteins whereby the variable (V) regions form the antigen-binding sites and the effector activities are mediated through the constant (C) regions2. This article will focus on the latter aspect, particularly the molecular evolutionary origins of the gene segments encoding Ig heavy (H) chains." (p. 543)
A model for the origin of the various immunoglobulins is constructed based on the phylogenies reviewed in the paper:
"A model for the evolution of the VH genes

From the evidence discussed above, a model for the evolutionary origins of VH and Ig isotypes is presented in Fig. 4. As originally proposed, the V and C domains arose by duplication of a primordial Ig domain3,13. The C domains duplicated and evolved independently to form the primordial prototype H-chain isotype." (p. 548)

Agrawal, A., Eastman, Q. M. and Schatz, D. G. (1998). "Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system." Nature 394(6695): 744-751. (PubMed | DOI | Journal | Google Scholar)

This study reports a major research finding that supported the transposon hypothesis for the origin of adaptive immunity. The authors found that the rearrangment-activating genes, RAG1+RAG2, could still perform both the excision and the insertion reactions, just like a free-living transposon.

Figure 7 is a nice color graphic of the transposon hypothesis.
"Our results are evidence in favour of the theory that a vital event in the evolution of the antigen-specific immune system was the insertion of a 'RAG transposon' into the germ line of a vertebrate ancestor14,41." (p. 750)

[References]

14. Thompson, C. B. New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3, 531-539 (1995).

15. Lewis, S. M. & Wu, G. E. The origins of V(D)J recombination. Cell 88, 159-162 (1997).

41. Sakano, H., Hüppi, K., Heinrich, G. & Tonegawa, S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 280, 288-294 (1979).

Plasterk, R. (1998). "Ragtime jumping." Nature 394(6695): 718-719. (PubMed | DOI | Journal | Google Scholar)

Summary of the Nature article Agrawal et al. (1998). While short and nontechnical, it is relevant to some of Behe's "search criteria" as he laid out during his sworn deposition for the Kitzmiller case. During his deposition in May 2005, Behe was quizzed about some of his claims about the immune system, and he was asked how he even knew what was in the literature since he wasn't familiar with the peer-reviewed articles that were presented then. Behe's answers (Behe deposition, pp. 231-233) were basically (1) he relies on other people to email him articles that meet his challenges, (2) articles on the evolution of the immune system would be big news, so he watches out for news articles in major scientific publications, and review articles in review journals and other scientific literature, and (3) he watches out for articles in popular scientific outlets such as the New York Times or Scientific American.

Plasterk's 1998 article in Nature is an example of case #2, which Behe missed. Many of the other articles in this bibliography are also review articles; one is even found in Annual Review of Immunology (Litman et al. 1999), and two are in Immunological Reviews (Cannon et al. 2004, Jones et al. 2004). Although not included in this bibliography, two 1996 articles in Scientific American on the evolution of the immune system are examples of case #3.

The Plasterk article begins:

"Transposons are generally considered the ultimate forms of selfish DNA -- a single gene (or sometimes a set of two or three genes) that spreads simply because it ensures its own replication. Indeed, the ability of transposons to encode one or more proteins that selectively replicate the transposon is enough to explain their existence. But selfish elements may also end up doing something useful for their host, and it has often been speculated that transposon jumping may have generated gene arrangements that opened new avenues in evolution. Examples of this are rare, but a spectacular case has now been discovered. On page 744 of this issue, David Schatz and his colleagues report that we owe the repertoire of our immune system to one transposon insertion, which occurred 450 million years ago in an ancestor of the jawed vertebrates. Vertebrates seem to have tamed this ancient transposon for generation of the immune repertoire, and the authors show that the RAG1 and RAG2 proteins (which mediate V(D)J joining) can still catalyse a full transposition reaction. A similar result has been independently obtained by Martin Gellert and co-workers2, and is reported in tomorrow’s issue of Cell."

[References]

1. Agrawal, A., Eastman, Q. M. & Schatz, D. G. Nature 394, 744-751 (1998).

2. Hiom, K., Melek, M. & Gellert, M. Cell 94, 463-470 (1998).

Vetvicka, V. and Síma, P. (1998). Evolutionary Mechanisms of Defense Reactions. Basel, Birkhäuser Verlag. (Library | Amazon | Google Print)

Vetvicka & Sima systematically review the immune systems of animals, starting with the earliest branches on the animal phylogenetic (sponges), through the various simple and complex invertebrates, the chordate relatives of vertebrates, the early diverging vertebrates such as the lampreys and hagfish, and ending with the "higher" vertebrates and their adaptive immune systems. Highly technical, focuses on immune system organs in addition to the cellular/molecular level. The primary themes are that: (1) immune system evolution must be considered in the context of ecological and morphological change in mammal groups; (2) there is a large degree of diversity in so-called "primitive" organisms, and there are many ways organisms survive without the "required" parts of vertebrate immunity.
"[B]asic research in comparative and evolutionary immunology has substantially contributed in many ways to the exciting progress that immunology has made in recent decades." (p. 187)

Lewis, S. M. (1999). "Evolution of Immunoglobulin and T-Cell Receptor Gene Assembly." Annals of the New York Academy of Sciences 870: 58-67. (PubMed | Journal | Google Scholar)

Another detailed review of the RAG transposon hypothesis by Susanna Lewis. It is a clear example of the increasing confidence that researchers in the field have about the transposon hypothesis. E.g., from the introductory section, entitled, "A transposon origin for V(D)J recombination":
"How such a singular mechanism for somatic cell differentiation arose has long been a puzzle.6 Although a multiplicity of site-specific recombination systems exist in bacteria, yeast, and protozoa, no other example apart from V(D)J recombination is known to operate in vertebrates. One speculation dating back to the time of the first molecular descriptions of immunoglobulin gene rearrangement is that the V(D)J recombination system may have evolved from a mobile element.7 Now, almost 20 years later, biochemical analyses of RAG1 and RAG2 have uncovered solid clues that this indeed may be the case." (p. 58)
Figure 4 contains a summary depiction of the transposon hypothesis. Lewis (1999) is especially noteworthy because it contains an uncannily predictive suggestion in the section suggesting further research avenues:
"THE NEXT STEP

It would be extremely useful if a contemporary version of the original RAG transposon could be identified. A distant cousin, with credentials, would greatly facilitate any attempts to reconstruct the lost history between the time the first RAG element took up residence in the vertebrate genome and the emergence of a developmental recombination system." (p. 65)
Exactly this was discovered six years later, in 2005 (Kapitonov & Jurka, 2005). Another cousin was discovered in 2006 (Fugmann, S. D., Messier, C., Novack, L. A., Cameron, R. A. and Rast, J. P. (2006). "An ancient evolutionary origin of the Rag1/2 gene locus." Proc Natl Acad Sci U S A 103(10): 3728-3733)
[References]

1. Marchalonis, J.J., S.F. Schluter, R.M. Bernstein, S. Shen & A.B. Edmundson. 1998. Phylogenetic emergence and molecular evolution of the immunoglobulin family. Adv. Immunol. 70: 417-506.

2. Gellert, M. 1997. Recent advances in understanding V(D)J recombination. Adv. Immunol. 64: 39-64.

[...]

6. Lewis, S. & G. Wu. 1997. The origins of V(D)J recombination. Cell 88: 159-162.

7. Sakano, H., K. Hüppi, G. Heinrich & S. Tonegawa. 1979. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 280: 288-294.

Litman, G. W., Anderson, M. K. and Rast, J. P. (1999). "Evolution of antigen binding receptors." Annual Review of Immunology 17: 109-147. (PubMed | DOI | Journal | Google Scholar)

This very long (38 pages) and technical review article cites 171 references, surveying all aspects of the origins of adaptive immunity, focusing on the ancestry and phylogeny of the receptors rather than the transposon hypothesis which is taken as confirmed.
"This review addresses issues related to the evolution of the complex multigene families of antigen binding receptors that function in adaptive immunity. [...] As of yet, homologous forms of antigen binding receptors have not been identified in jawless vertebrates; however, acquisition of large amounts of structural data for the antigen binding receptors that are found in a variety of jawed vertebrates has defined shared characteristics that provide unique insight into the distant origins of the rearranging gene systems and their relationships to both adaptive and innate recognition processes." (p. 109)

"Further clarification of the origins and interrelationships of these putative receptors will come through phylogenetic comparisons between rearranging and nonrearranging antigen binding receptors found in jawed vertebrates. Such analyses will also be significant in terms of designing strategies for identification of related systems in agnathans, lower chordates, hemichordates, and echinoderms. The recent discovery that RAG1 and RAG2 proteins together constitute a transposase, capable of excising a piece of DNA containing recombination signals from a donor site and inserting into a target DNA molecule, has enormous bearing on mechanisms whereby nonrearranging receptors diverged into the rearranging antigen binding receptor genes (171)." (p. 139)

[References]

171. Agrawal A, Eastman QM, Schatz DG. 1998. Transposition mediated by the V(D)J recombination proteins RAG1 and RAG2: implications for the origins of the antigen-specific immune system. Nature 394:744-51

Schatz, D. G. (1999). "Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system." Immunologic Research 19(2-3): 169-182. (PubMed | Google Scholar)

Technical review of the tranposon hypothesis. The abstract summarizes Schatz's main point:
"The hypothesis that RAG1 and RAG2 arose in evolution as components of a transposable element has received dramatic support from our recent finding that the RAG proteins are a fully functional transposase in vitro."
Noteworthy in the article is Schatz's description of Sakano et al. (1979) as advancing a "prophetic hypothesis":
"When examined in their germline configuration, the RSSs flanking V and J constitute an inverted repeat, much like that found at the end of transposons, and this realization led to the prophetic hypothesis, in 1979, that insertion of a transposable element into an ancient receptor gene exon was responsible for the generation of split antigen receptor genes during evolution (5)." (p. 170)

[Reference cited]

5 Sakano H, Hüppi K, Heinrich G, Tonegawa S: Sequences at the somatic recominbation sites of immunoglobulin light-chain genes. Nature 1979;280:288-294.

Schluter, S. F., Bernstein, R. M., Bernstein, H. and Marchalonis, J. J. (1999). "'Big Bang' emergence of the combinatorial immune system." Developmental and Comparative Immunology 23(2): 107-111. (PubMed | DOI | Journal | Google Scholar)

Basic review of the transposon hypothesis. The title and various quotes are the kind of thing that are commonly quote-mined by creationists, e.g., "Thus, the Big Bang must have occurred in the extremely short time of emergence of jawed vertebrates from their ostracoderm ancestors." (p. 107) However, it is worth noting that "extremely short" means about 50 million years in this context. And, the whole point of the article is that the transpson hypothesis, where a prokaryotic transposon jumped into the vertebrate genome, is what explains the "big bang" in question.

For example:
"We [1, 2, 20] and others [6, 8, 33, 34] have hypothesized that the event that catalyzed the explosive burst of the generation of combinatorial immunity (Fig. 1) was the horizontal transfer of genes from microbes and/or fungi enabling site-specific recombination of DNA. Because retroviruses have long been known to insert into mammalian chromosomes and defective pieces of retrotransposons have been found in lower deuterostomes [33, 34], sharks [35], turtles [36] and chickens [37], and retrotransposons are widely distributed among teleost fish [38], we tentatively suggested that retroviruses may have played a role in this transition. However, transposons capable of directly modifying DNA [39, 40] may also play a substantial role. It was first recognized by Thompson [6] that the gene cluster specifying RAG1 and RAG2 resembles a disassociated transposon, thus suggesting a transposon origin for these genes. Direct in vitro experimental support for this hypothesis was recently provided in two reports, Agrawal et al., [41] and Hiom et al.[42]. These groups showed that recombinant RAG1 and RAG2 proteins together could cleave a fragment of DNA flanked by RSS (recombinant signal sequence) sites and mediate its insertion into a plasmid, thus directly demonstrating that RAG proteins can express transposase activity." (p. 108)
Figure 2 gives a depiction of the transposon hypothesis. More evidence for the transposon hypothesis is given on the next pages:
"IHF [Integration Host Factor] binding sites in some transposons (e.g. TnA family) occur adjacent to transposase binding sites, suggesting that the RAGI/RAGII recombination system arose from an ancestral system in a transposon or retrotransposon." (pp. 109-110)

[References]

[1] Marchalonis JJ, Schluter SF, Bernstein RM, Edmundson AB. Phylogenetic emergence and molecular evolution of the immunoglobulin family. Adv. in Immunol. 1998; 70:417-506.

[2] Marchalonis JJ, Schluter SF. A stochastic model for the rapid emergence of specific vertebrate immunity incorporating horizontal transfer of systems enabling duplication and combinatorial diversification. J. Theo. Biol. 1998; 193:429-444.

[3] Marchalonis JJ, Schluter SF. On the relevance of invertebrate recognition and defense mechanisms to the emergence of the immune response of vertebrates. Scand. J. Immunol. 1990;32:13-20.

[4] Klein J. Homology between immune responses in vertebrates and invertebrates: does it exist? Scand. J. Immunol. 1997;46:558-564.

[5] Hughes AL, Yeager M. Molecular evolution of the vertebrate immune system. BioEssays 1997;19:777-786.

[6] Thompson CB. New Insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 1995;3:531-539.

[7] Medzhitov R, Janeway CA. Innate Immunity: The virtues of a nonclonal system of recognition. Cell 1997;91:295-298

[8] Bartl S, Baltimore D, Weissman IL. Molecular evolution of the vertebrate immune system. Proc. Natl. Acad. Sci. USA 1994;91:10769-10770.

[9] Habicht GS. Primordial immunity: foundations for the vertebrate immune system. In: Beck G, Cooper EL, Habicht GS, Marchalonis JJ, editors. Primordial Immunity: Foundations for the Vertebrate Immune System, vol. 712. New York: New York Academy of Sciences, 1994:ix-xi.

[41] Agrawal A, Eastman QM, Schatz DG. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 1998;394:744-751.

[42] Hiom K, Melek M, Gellert M. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 1998;94:463-470.

Du Pasquier, L. (2000). "The Phylogenetic Origin of Antigen-Specific Receptors." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 159-185. (Library | PubMed | Amazon | Google Print)

Highly technical review of the origin of the receptor genes, starting with Ig homologs in invertebrates, and then looking at the relationships between the various immune system genes within vertebrates.
"Fig. 10. Origin and evolution of Igsf members with V and C1 domains. A hypothesis taking into account the genetic linkages and the homologies presented in this chapter." (pp. 178-179)

"This survey reminds us that V domains are very ancient and exist in the most primitive Metazoa. [...] A model (Fig. 10) is presented accounting for many of the linkages and homologies described." (p. 182)

Du Pasquier, L. and Litman, G. W., eds. (2000). Origin and Evolution of the Vertebrate Immune System. Current Topics in Microbiology and Immunology. Berlin, Springer. (Library | Publisher | Amazon | Google Print)

This edited book in the Current Topics in Microbiology and Immunology series contains 14 articles by 33 contributors on the evolutionary origin of the immune system. It is a thorough survey of the evolution of the major parts of the immune system as of 2000. Most of the articles are very technical. Despite this, the Preface reads,
"This book is by no means comprehensive and can be complemented by reading recent issues of Immunological Reviews (nos. 166, Immune systems of ectothermic vertebrates, and 167, Genomic organisation of the MHC: structure, origin, and function)." (p. vi)

"The quantity of information concerning vertebrate immunity from developmental and molecular perspectives is enormous, and offers an excellent opportunity to study the evolutionary behavior of complex molecular networks. As more sea urchin genes that are homologous to genes of the vertebrate immune system are isolated, it is becoming clear that the phylogenetic position of the echinoderms will truly enable the creation and testing of hypotheses of large scale immune system evolution." (Chapter 1, "New approaches Towards and Understanding of Deuterostome Immunity", p. 5)
Also, from Chapter 1, Section 4, "The Evolution of Complex Systems":
"Subsystems of a complex immune system may evolve independently from one another, and as a first step towards understanding system-wide evolution these points of disjunction must be characterized." (Chapter 1, "New approaches Towards and Understanding of Deuterostome Immunity", p. 12)

Hansen, J. D. and McBlane, J. F. (2000). "Recombination-Activating Genes, Transposition, and the Lymphoid-Specific Combinatorial Immune System: A Common Evolutionary Connection." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 111-135. (Library | PubMed | Amazon | Google Print)

This is one of three articles from the volume, "Origin and Evolution of the Vertebrate Immune System," which were included in the article list. The book itself is listed in the book list. The three articles were included in the article bibliography because they were particularly useful summaries of the evolution of key pieces of adaptive and innate immunity.

This article is a technical review of the evolution of V(D)J recombination and evolution. Section 4, "Origins of Rag1 and Rag2," contains the now-familiar review of the development and confirmation of the transposon hypothesis:
"The genomic organization of the Ig and TCR loci themselves first hinted at a possible link between the V(D)J recombination mechanism and DNA transposition (Sakano et al. 1979). Detailed knowledge of the Rag genes and the biochemical activities of their products strengthened this comparison (Lewis and Wu 1997; Thompson 1995). Recent biochemical data sealed this functional link, strongly suggesting that the Rag genes appeared in the vertebrate genome about 450 MYA as passengers in a transposon. The evidence accumulated to date in favor of the Rag transposon comes from 4 main sources..." (p. 122)
The lines of evidence presented should be familiar at this point; however, the authors highlight the importance of the fourth line of evidence, "DNA transposition by the Rag proteins":
"The most dramatic parallel between DNA transposition and V(D)J recombination was shown recently by two groups (Agrawal et al. 1998; Hiom et al. 1998; reviewed in Plasterk 1998; Roth and Craig 1998). In these studies, the Rag proteins performed not only DNA cleavage at the RSS, but also transpositional insertion of the RSS-containing cleavage products into unrelated target DNA (Fig. 4)." (p. 123)
The authors continue:
"The structure of the antigen receptor loci is itself a compelling argument in favor of a transpositional origin for the immune system (Sakano et al. 1979), with both V(D)J recombination and DNA transposition involving a pair of inverted repeats at the ends of the recombining agent." (p. 123)
On p. 125, Figure 5 shows the "Rag transposon model".
The concluding section of the article reviews what has gone before: "We describe multiple lines of evidence above which suggest that the Rag genes were introduced into the vertebrate genome over half a billion years ago as part of an ancestral transposon." (p. 130)
...and follows it up with a summary of the model.

Lewis, S. M. and Wu, G. E. (2000). "The old and the restless." Journal of Experimental Medicine 191(10): 1631-1636. (PubMed | DOI | Journal | Google Scholar)

Another review paper on the RAG transposon hypothesis from Lewis and Wu. Figure 2 contains a usefully clear figure depicting the hypothesis. The second paragraph sums up the development of the transposon hypothesis:
"As recently as only a few years ago, any real information bearing on the actual genesis of the V(D)J recombination system seemed to be irretrievably lost. However, as more was learned about the molecular genetic and biochemical properties of the V(D)J recombination proteins, termed recombination activating gene (RAG)-1 and RAG-2, tantalizing suggestions of a transposon origin began to emerge. These clues included the following: first, the fact that the genes encoding RAG-1 and RAG-2, which are unrelated in sequence, are tightly linked, and as such share this property with genes that are known to undergo horizontal transfer (4). Second, the chemical mechanism of the recombination reaction, where DNA strand breakage and rejoining is accomplished through one step transesterification reactions, was like that of several well-described mobile elements (5). Finally, a surprising finding further indicated that RAG-1 and RAG-2 might have once been part of a transposon when two groups independently demonstrated that purified RAG-1 and RAG-2 proteins have a latent ability to carry out the transposition of DNA (6, 7)." (p. 1631)

"Thus, the unusual in vitro ability of RAG-1 and RAG-2 to do two quite different things, and in particular to transpose DNA, provided strong support for the original speculation that the V(D)J recombination system used to be a transposable element (3)." (p. 1631)

[References]

1. Marchalonis, J.J., S.F. Schluter, R.M. Bernstein, S. Shen, and A.B. Edmundson. 1998. Phylogenetic emergence and molecular evolution of the immunoglobulin family. Adv. Immunol. 70:417-506.

2. Litman, G.W., M.K. Anderson, and J.P. Rast. 1999. Evolution of antigen binding receptors. Annu. Rev. Immunol. 17:109-147.

3. Sakano, H., K. Huppi, G. Heinrich, and S. Tonegawa. 1979. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature. 280:288-294.

4. Oettinger, M.A., D.G. Schatz, C. Gorka, and D. Baltimore. 1990. Rag-1 and Rag-2, adjacent genes that synergistically activate V(D)J recombination. Science. 248:1517-1523.

5. van Gent, D.C., D. Mizuuchi, and M. Gellert. 1996. Similarities between initiation of V(D)J recombination and retroviral integration. Science. 271:1592-1594.

6. Agrawal, A., Q.M. Eastman, and D.G. Schatz. 1998. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature. 394:744-751.

7. Hiom, K., M. Melek, and M. Gellert. 1998. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell. 94:463-470.

Nonaka, M. (2000). "Origin and evolution of the Complement System." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 37-50. (Library | PubMed | Amazon | Google Print)

Nonaka regularly authors or coauthors articles reviewing the evolutionary origin of the innate immune system. This article surveys the complement systems of vertebrates and invertebrates and focuses on the origin of the B and C2 proteins which help activate the complement system, and the MASP proteins, mammalian serine proteases which actually have homologs in groups as distant as ascidians.
"This chapter discusses recent progress in understanding the evolution of the complement system mainly in invertebrates and lower vertebrates." (p. 38)

"The hypothetical story of the origin and evolution of the complement system has been composed from data discussed above (Fig. 3). The birth of the complement system is located somewhere during evolution of invertebrate phyla, although the exact stage at which the complement system was established must still be clarified. The original complement system most probably resembled the LeP and AP of the mammalian complement system. Lectin-based recognition by MBL, followed by the activation of MASP, B, and then C3, covalent binding of C3 to foreign particles, and finally phagocytosis of C3-tagged foreign particles by phagocytes with C3 receptors on their surface seem to be the most probable constitution of the original complement system." (p. 46)

Opal, S. M. (2000). "Phylogenetic and functional relationships between coagulation and the innate immune response." Critical Care Medicine 28(9): S77-S80. (PubMed | Journal | Google Scholar)

This article reviews the evolutionary and physiological relationships between the blood-clotting cascade (coagulation) and the the inflammatory cascade which initiates innate immune responses.
"The simultaneous activation of the inflammatory response and the coagulation system after injury is a phylogenetically ancient, adaptive response that can be traced back to the early stages of eukaryotic evolution." (p. S77)

"Concluding Remarks. The coagulation system is integrally related to the innate immune response, and its activation and regulation are dependent on local and systemic immune responses. The simultaneous activation of clotting and the innate immune response is a phylogenetically ancient host response to tissue injury and is a primary survival strategy throughout vertebrate evolution." (p. S79)

Richards, M. H. and Nelson, J. L. (2000). "The Evolution of Vertebrate Antigen Receptors: A Phylogenetic Approach." Molecular Biology and Evolution 17(1): 146-155. (PubMed | Journal | Google Scholar)

This research article explores the phylogeny of somatically rearranging antigen receptors, seeking the most basal groups.
"It is now clear that indirect, MHC-restricted antigen recognition must be a derived characteristic of [alpha][beta] T cells, while [gamma][beta] T cells exhibit the primitive condition of direct antigen binding. This removes a major stumbling block in several schemes for the evolution of vertebrate immune systems (e.g., Stewart 1992), because it shows that the origins of diverse T-cell characteristics, such as antigen recognition and effector functions, may be separate, independent evolutionary events. Continued phylogenetic analysis of TCR and Ig relationships, especially as more suitable outgroup sequences are obtained from organisms such as cyclostomes or sharks, should continue to improve our understanding of immune system evolution." (p. 154)
The reference to Stewart is: Stewart, J. 1992. Immunoglobulins did not arise in evolution to fight infection. Immunology Today 13:396-399. Stewart is also the author of the 1994 book The Primordial VRM System and the Evolution of Vertebrate Immunity.

Roth, D. B. (2000). "From lymphocytes to sharks: V(D)J recombinase moves to the germline." Genome Biology 1(2): 1014.1011-1014.1014. (PubMed | DOI | Journal | Google Scholar)

This article reviews the transposon model for the origin of rearranging receptors, and also explores the impact that the V(D)J recombinase may have had as an evolutionary force.
"Early on, it was suggested that the V(D)J recombination system might have arisen by the fortuitous integration of a transposable element into an ancestral antigen-receptor gene [14]. This hypothesis was strengthened by the discovery that the RAG genes are tightly linked [7], and by the finding that the RAG proteins can act as a transposase. Thus, a plausible model for the acquisition of the V(D)J recombination system during vertebrate evolution is the integration of a transposable element carrying the linked RAG genes into a primordial antigen-receptor gene in an ancestral jawed vertebrate, approximately 450 million years ago (reviewed in [1,11]). Presumably, this initial integration event created the first rearranging antigen-receptor gene; subsequent gene duplication events then created the multiple immunoglobulin and T-cell receptor loci." (p. 1014.2)

[Notable References]

1. Thompson CB: New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 1995, 3:531-539.

2. Litman GW, Anderson MK, Rast JP: Evolution of antigen binding receptors. Annu Rev Immunol 1999, 17:109-147.

3. Marchalonis JJ, Schluter SF, Bernstein RM, Shen S, Edmundson AB: Phylogenetic emergence and molecular evolution of the immunoglobulin family. Adv Immunol 1998, 70:417-506.

4. Lee SS, Fitch D, Flajnik MF, Hsu E: Rearrangement of immunoglobulin genes in shark germ cells. J Exp Med 2000, 191:1637-1648.

[...]

7. Oettinger MA, Schatz DG, Gorka C, Baltimore D: RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 1990, 248:1517-1523.

[...]

11. Hansen JD, McBlane JF: Origin and evolution of the vertebrate immune system. Curr Topics Microbiol Immunol 2000, 248:111-135.

12. Agrawal A, Eastman QM, Schatz DG: Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 1998, 394:744-751.

13. Hiom K, Melek M, Gellert M: DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 1998, 94:463-470.

14. Sakano H, Huppi K, Heinrich G, Tonegawa S: Sequences at the somatic recombination sites of immunoglobulin light chain genes. Nature 1979, 280:288-294.

Vaandrager, J.-W., Schuuring, E., Philippo, K. and Kluin, P. M. (2000). "V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma." Blood 96(5): 1947-1952. (PubMed | Journal | Google Scholar)

The results of this research article give indirect evidence that transposition reactions mediated by RAGs can occur not just in vitro, but within mammalian cells, further supporting the transposon hypothesis.

Du Pasquier, L. (2001). "The immune system of invertebrates and vertebrates." Comparative Biochemistry and Physiology Part B Biochemistry & Molecular Biology 129(1): 1-15. (PubMed | DOI | Journal | Google Scholar)

Review of current comparative immunology. Excellent figures show the variability and repeated themes (due to duplication and combination of genes) in various immune systems. Fig. 3 shows the repeated use of proteins in the immunoglobulin superfamily in invertebrates.

Figure 2 mentions the transposon hypothesis:
"The introduction of what nowadays behaves as a site sensitive to the RAG enzyme is supposed to have occurred via the introduction of a transposon (Rougeon, 1986; Thompson, 1995)." (p. 5)
The text does also:
"It is as if a 'horizontal' acquisition of a transposon had occurred at some point during the history of the vertebrates (Thompson, 1995). The receptor gene structure itself, in the region where the rearrangement takes place, suggests the introduction of a transposon. The recombination signal sequences flank the gene segments (V and J in the light chain for instance) in the same way as the LTR does in a transposon (Hansen and McBlane, 2000). In principle, RAG activity is confined to lymphocytes but the existence of germ-line rearrangements in light chain genes in the shark suggests that RAG (Lee et al., 2000) is still an active force changing the genome in some vertebrates."

[References]

Hansen, J.D., McBlane, J.F., 2000. Recombination-activating genes, transposition, and the lymphoid-specific combinatorial immune system: a common evolutionary connection (In Process Citation). Curr. Top. Microbiol. Immunol. 248, 111-135.

Lee, S.S., Fitch, D., Flajnik, M.F., Hsu, E., 2000. Rearrangement of immunoglobulin genes in shark germ cells (see comments). J. Exp. Med. 191, 1637-1648.

Rougeon, F., 1986. La diversité des anticorps. La Recherche 17, 680-689.

Thompson, C.B., 1995. New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3, 531-539.

Nonaka, M. and Miyazawa, S. (2001). "Evolution of the Initiating Enzymes of the Complement System." Genome Biology 3(1): 1001.1001-1001.1005. (PubMed | DOI | Journal | Google Scholar)

Technical review of the origin of the innate (non-adaptive) immune system.

"Figure 2 A proposal for the evolution of the MASP-113, MASP-2, C1r and C1s genes." (p. 1001.3)
"The primitive complement system

As discussed here, the complement system seems to have a more ancient origin in evolution than adaptive immunity; the latter seems to have been established only from jawed vertebrates onwards. The central component of the complement system, the C3 protein on which the three activation pathways discussed here converge, has been identified in jawless vertebrates, the lamprey [13] and hagfish [14], as well as in deuterostome invertebrates, amphioxus (a cephalochordate) [15], ascidian (urochordate) [16] and sea urchin (echinoderm) [17]. Although C3- or complement-like molecules of insects show functional similarity with deuterostome C3, there is no shared derived structural character between them, indicating that the deuterostome C3 and insect C3-like molecules derived independently from their common ancestor, [alpha]2-macroglobulin. Thus, the authentic complement system seems to have been established in the deuterostome lineage; the classical pathway of complement activation was then acquired in the jawed vertebrate lineage, at the time adaptive immunity arose." (p. 1001.4)

Cannon, J. P., Haire, R. N. and Litman, G. W. (2002). "Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate." Nature Immunology 3(12): 1200-1207. (PubMed | DOI | Journal | Google Scholar)

A key research article finally presenting evidence of a non-rearranging receptor closely related to the vertebrate rearranging receptors, in the lancelet (a cephalochordate which lacks adaptive immunity). This is important because it provides one of the homologs that scientists had been seeking for years. It also shows that even without rearranging receptor capability, selection favored diverse receptors:
"Thus, multigenic families encoding diversified V regions exist in a species lacking an adaptive immune response." (p. 1200)

Kaufman, J. (2002). "The origins of the adaptive immune system: whatever next?" Nature Immunology 3(12): 1124-1125. (PubMed | DOI | Journal | Google Scholar)

In this News & Views article in Nature Immunology, Kaufman expresses wonderment at the results of Cannon et al. (2002).
"Indeed, the initial event that enabled the emergence of the adaptive immune system is thought to have been the insertion of a transposon into a previously undisrupted V-like exon of an Ig domain-containing gene2,3,5. But in which Ig gene did the insertion occur?" (p. 1124)

"The obvious approach to answer these questions is to search for a V-like Ig-containing gene in a jawless vertebrate or a nonvertebrate chordate." (p. 1124)

"The discovery of a V-like Ig multigene family in the protochordate amphioxus provides new insights into the evolution of the adaptive immune response." (p. 1124, summary)

[References]

1. Cannon, J. P., Haire, R. N. & Litman, G. L. Nature Immunol. 3, 1200-1207 (2002).

2. Litman, G. W., Anderson, M. K., & Rast, J. P., Annu. Rev. Immunol. 17, 109-147 (1999).

3. Flajnik, M. F. & Kasahara, M. Immunity 15, 351-362 (2001).

[...]

5. Tonegawa, S. Nature 302, 575-581 (1983).

Krem, M. M. and Di Cera, E. (2002). "Evolution of enzyme cascades from embryonic development to blood coagulation." Trends in Biochemical Sciences 27(2): 67-74. (PubMed | DOI | Journal | Google Scholar)

Article reviews the evolutionary and physiological relationships between the blood-clotting cascade and the complement cascade of the innate immune system.
"Here, it is proposed that a single ancestral developmental/immunity cascade gave rise to the protostome and deuterostome developmental, clotting, and complement cascades. Extensive similarities suggest that these cascades were built by adding enzymes from the bottom of the cascade up and from similar macromolecular building blocks." (p. 67)
Figure 2 (p. 71) shows proposed relationships.
"Fig. 2. Evolutionary changes producing developmental, immune and clotting cascades."

"The emergence of the advanced deuterostome complement system, featuring both the classical and alternative pathways, occurred by duplication of primitive complement proteins and recruitment of new proteases from the pool of ancestral building blocks." (p. 73)

"The modern mammalian clotting cascade was completed by the addition of serine proteases such as factors XI and XII, and cofactors such as factors V and VIII, which conferred additional levels of positive and negative feedback regulation." (p. 73)

Laird, D. J. (2002). "Immune System." Encyclopedia of Evolution. Edited by M. Pagel. Oxford, Oxford University Press. 2: 558-564. (Library | Publisher | Amazon | Google Print)

Basic introduction to the immune system, but in a thoroughly evolutionary context. Figure 4 (p. 563) depicts the progressive aquisition of features as one moves closer to mammals in the vertebrate phylogeny. It is noteworthy that the transposon hypothesis is sufficiently well-accepted, and well-known, to make it into a general encyclopedia on evolution. Furthermore, this is another example of the secondary literature that is readily available to anyone seriously looking into evolutionary immunology.
"Structures of the Vertebrate Immune System. Despite the quantity of immune receptors, signalling molecules, and serum factors that carry out antigen recognition and the accompanying inflammatory response, these structures share much in common. Protein motifs such as the immunoglobulin fold, which appears in Ig, TCR, natural killer (NK) cell receptors, MHC receptors, complement proteins, and adhesion molecules, imply extraordinary recycling and even a common origin during evolution. The hypothesis that a primordial immunoglobulinlike receptor gave rise to the rearranging receptors of lymphocytes has inspired the study of Ig, TCR, and other immune receptors of primitive vertebrates. This section focuses on the evolution of the main components of the adaptive immune system, unique to jawed vertebrates." (p. 559)

"The sudden appearance of RAG in Chondrychthyes, coupled with their peculiar genetic features (they lack introns and are adjacent in most species) suggests their origin as a retrotransposon, or a foreign DNA element introduced by a virus some 500 million years ago." (p. 561)

"The origin of adaptive immunity can be approached from many angles. The genomic approach was first employed by Masanori Kasahara, who hypothesized that genome duplications in vertebrate ancestors paved the way for the molecular experimentation that gave rise to this system. Comparison of MHC loci across vertebrate species provides clues about how and when this chromosomal region of immune and nonimmune genes was assembled. The study of RAG structure and mechanism across vertebrates fuels the theory that receptor genes of the adaptive immune system first arose by transposon-induced shuttling of duplicated segments of DNA. Phylogenetic data estimate the appearance of RAG in a vertebrate ancestor about 500 million years ago, approximately coincidental with the last hypothesized genome duplication and the origins of TCR, Ig, and MHC receptors. Another strategy is the reconstruction of the hypothetical ancestral receptor through discovery of surviving remnants, such as nonrearranging immunoglobulin domain receptors in vertebrates and invertebrates alike. Candidates include the paired Ig-like receptors, whose role as inhibitory and activating receptors for MHC I and MHC I-like molecules in mammals suggests their involvement in ancient self-nonself recognition. A number of other Ig-type nonrearranging receptors, such as the NAR in sharks and the NITR in pufferfish, contribute to our understanding of receptor evolution." (p. 564)

Marchalonis, J. J., Jensen, I. and Schluter, S. F. (2002). "Structural, antigenic and evolutionary analyses of immunoglobulins and T cell receptors." Journal of Molecular Recognition 15(5): 260-271. (PubMed | DOI | Journal | Google Scholar)

Long review of the work of the Marchalonis lab.
"This laboratory has focused upon the structure, function and evolution of antibodies and T cell receptors for more than 25 years." (p. 260)
Evolution played a key role in the lab's study of antigen receptors. The article is interesting because it highlights the interrelationship between structural and evolutionary studies -- homology and phylogeny allow structural knowledge gained in one lineage (e.g., sharks) to be applied to another that is more medically relevant (such as humans). The authors also note that sharks were chosen as the study organisms of choice because any features conserved across the evolutionary distance between sharks and humans is likely to be functionally important:
"We have studied antibodies, antibody production and cellular immunity in representatives of all the vertebrate classes, but we have chosen to concentrate our studies of antibody and T cell receptor structure on a comparison between the genes and molecules of sharks and humans because these two species represent the most evolutionarily divergent organisms to express the complete combinatorial immune system consisting of immunoglobulins, major histocompatability complex antigens, T cell receptors, and recombination activator genes (DuPasquier and Flajnik, 1999; Litman et al., 1999; Marchalonis and Schluter, 1998; Marchalonis et al., 1998a)." (p. 261)

Marchalonis, J. J., Kaveri, S., Lacroix-Desmazes, S. and Kazatchkine, M. D. (2002). "Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system." FASEB Journal 16(8): 842-848. (PubMed | Journal | Google Scholar)

Technical review of several aspects of the origin of adaptive immunity, including the capacity for receptor diversity and its selective value, and the importance of clonal selection during maturation of specific antibodies. The quick review of the transposon hypothesis is quoted below:
"The complete [Combinatorial Immune Response, CIR] ensemble is present in all jawed vertebrates (8-10). The system emerged rapidly and accidentally in evolution (3, 14, 18) probably as the result of horizontal transfer of microbial genes for site-specific recombination (4-6, 18, 19). Ab initio, the CIR was neither a defense mechanism nor part of an internal regulatory system (20), but its unparalleled capacity to generate recognition molecules in real time gave it the potential to function effectively in both contexts. The CIR co-opted preexisting cellular and humoral mechanisms for activation, differentiation, and destruction of bound targets including the NF[kappa]B pathway, the IL-1/TOLL receptor complex, and interaction with more ancient complement components to initiate cytolysis, killing, and trigger inflammation (12-15)." (p. 843)

[References]

3. Marchalonis, J. J., and Schluter, S. F. (1998) A stochastic model for the rapid emergence of specific vertebrate immunity incorporating horizontal transfer of systems enabling duplication and combinatorial diversification. J. Theo. Biol. 193, 429-444

4. Bernstein, R. M., Schluter, S. F., Bernstein, H., and Marchalonis, J. J. (1996) Primordial emergence of the recombination activating gene 1 (RAG1): Sequence of the complete shark gene indicates homology to microbial integrates. Proc. Natl. Acad. Sci USA 93, 9545-9459

5. Hiom, K., Melek, M., and Gellert, M. (1998) DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94, 463-470

6. Agrawal, A., Eastman, Q. M., and Schatz, D. G. (1998) Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature (London) 394, 744-751

7. Burnet, F. M. (1959) The Clonal Selection, Vanderbilt University Press, Nashville, Tennessee

8. Marchalonis, J. J., Schluter, S. F., Bernstein, R. M., and Hohman, V. S. (1998) Antibodies of sharks: revolution and evolution. Immunol. Rev. 166, 103-122

9. Litman, G. W., Anderson, M. K., and Rast, J. P. (1999) Evolution of antigen binding receptors. Annu. Rev. Immunol. 17, 109-147

10. DuPasquier, L., and Flajnik, M. (1999) Origin and evolution of the vertebrate immune system. In Fundamental Immunology (Paul, W. E., ed) pp. 605-650, Lippincott-Raven, Philadelphia

12. Fearon, D., and Locksley, R. M. (1996) The instructive role of innate immunity in the acquired immune response. Science 272, 50-53

13. Meister, M., Hetru, C., and Hoffman, J. A. (2000) The antimicrobial host defense of Drosophila. Curr. Top. Microbiol. Immunol. 248, 17-36

14. Marchalonis, J. J., and Schluter, S. F. (1990) On the relevance of invertebrate recognition and defense mechanisms to the emergence of the immune response of vertebrates. Scand. J. Immunol. 32, 13-20

15. Medzhitov, R., and Janeway, C. A. (1997) Innate Immunity: The virtues of a nonclonal system of recognition. Cell 91, 295-298

17. Good, R. A., and Papermaster, B. W. (1964) Ontogeny and phylogeny of adaptive immunity. Adv. Immunol. 4, 1-115

18. Schluter, S. F., Bernstein, R. M., Bernstein, H., and Marchalonis, J. J. (1999) 'Big Bang' emergence of the combinatorial immune system. Dev. Comp. Immunol. 23, 107-111

19. Plasterk, R. (1998) V(D)J recombination. Ragtime jumping. Nature (London) 394, 744-751

20. Stewart, J. (1992) Immunoglobulins did not arise in evolution to fight infection. Immunol. Today 13, 396-399

Clatworthy, A. E., Valencia, M. A., Haber, J. E. and Oettinger, M. A. (2003). "V(D)J recombination and RAG-mediated transposition in yeast." Molecular Cell 12(2): 489-499. (PubMed | DOI | Journal | Google Scholar)

This paper showed for the first time that RAG1 and RAG2 can act as a bona fide transposase in eukaryotic (yeast) cells, mediating the integration in the genome of an excised DNA fragment. The results confirmed another long-sought prediction of the transposon hypothesis:
"Here, we show that expression in Saccharomyces cerevisiae of murine RAG1 and RAG2, the lymphoid-specific components of the V(D)J recombinase, is sufficient to induce V(D)J cleavage and rejoining in this lower eukaryote." (p. 489)

Flajnik, M. F., Miller, K. and Du Pasquier, L. (2003). "Evolution of the Immune System." Fundamental Immunology. Edited by W. E. Paul. Philadelphia, Lippincott Williams & Wilkins: 519-570. (Library | Amazon | Google Print)

This 51-page review of evolutionary immunology references 213 citations. Technical, but very useful tables and graphics showing how the major features of the vertebrate immune system are gradually acquired in organisms getting closer in the phylogenetic tree to vertebrates.
"As predicted over 10 years ago by Zasloff (2), it is informative from both intellectual and applied viewpoints to understand how all living things defend themselves; few would argue against the premise that studies of Drosophila humoral immunity has fueled great interest in innate immunity, both for its own sake and in the way it regulates adaptive immunity (R3)." (p. 521)
Regarding the transposon hypothesis for the origin of the Recombination-Activating Genes, RAG1 and RAG2, Flajnik et al. write,
"It seems that a 'horizontal' acquisition of a RAG-laden transposon occurred at some point during the history of the vertebrates (R156, 202). The structure of the receptor gene itself, in the region where rearrangements occur, suggests the introduction of a transposon." (p. 562)
The article also suggests future research directions:
"Further molecular studies in hagfish and lamprey and in non-vertebrate deuterostomes will perhaps permit a better understanding of the events leading to the emergence of the adaptive immune system." (p. 566)
Note that in May 2005, a "free-living" transposon relative of RAG1 was discovered in a tunicate, a non-vertebrate deuterostome (Kapitonov and Jurka, 2005).

Just while this review article was being written, seven new research papers came out which the authors saw fit to mention in an addendum, "Publications Worth Noting."
[References cited]

R2. Jacob L, Zasloff M. Potential therapeutic applications of magainins and other antimicrobial agents of animal origin. Ciba Found Symp 1994; 186:197-216.

R3. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002; 20:197-216.]

R156. Hansen, J. D., McBlane, J. F. Recombination-activating genes, transposition, and the lymphoid-specific combinatorial immune system: a common evolutionary connection. Current Topics in Microbiology and Immunology 2000; 248:111-135.

R202. Agrawal A., Eastman Q. M., Schatz D. G. Transposition mediated by RAG1 and RAG2 and its implication for the evolution of the immune system. Nature. 1998; 394:744-751.

Market, E. and Papavasiliou, F. N. (2003). "V(D)J Recombination and the Evolution of the Adaptive Immune System." PLoS Biology 1(1): 24-27. (PubMed | DOI | Journal | Google Scholar)

A short review of recombination, and its evolutionary origin from a transposon. Included in the very first issue (volume 1, number 1) of the journal Public Library of Science: Biology. The entire contents of this journal are available free online.

The article notes that RAGs are indispensable for receptor gene rearrangement -- section heading: "RAGs: Indispensable for V(D)J Recombination" (p. 26)

However, despite the claims of antievolutionists, it is clear that RAGs evolved anyway:
"An Evolutionary Model of V(D)J Recombination

From the discovery of the RAG genes on, investigators have suspected that V(D)J recombination may be the result of the landing of a transposable genetic element (a "jumping gene" or transposon) into the vertebrate genome. The clues were many. Firstly, the compact organization of the RAG locus resembles a transposable element (Schatz et al. 1989). Secondly, RAGs cut the DNA after binding RSSs throughout the BCR and TCR loci (Gellert 2002). RSSs resemble the ends of other transposable elements. Biochemically, the reaction shares characteristics with enzymes found in other transposable elements (Gellert 2002). Finally, these genes appear abruptly in evolution: they are present in the jawed vertebrates (like the shark), but not in more ancient organisms (Schluter et al. 1999).

A current model is that an ancient transposon containing the RAG genes flanked by RSS ends "jumped’" into an area of the vertebrate lineage containing a primordial antigen receptor gene, separating it into pieces. When the transposon lifted off, it left the RSSs behind. Multiple rounds of transposition and duplication eventually gave rise to our TCR and BCR loci." (p. 27)

[References]

Gellert M (2002) V(D)J recombination: RAG proteins, repair factors, and regulation. Annu Rev Biochem 71: 101-132.

Schatz DG, Oettinger MA, Baltimore D (1989) The V(D)J recombination activating gene, RAG-1. Cell 59: 1035-1048.

Schluter SF, Bernstein RM, Bernstein H, Marchalonis JJ (1999) 'Big Bang' emergence of the combinatorial immune system. Dev Comp Immunol 23: 107-111.

Messier, T. L., O'Neill, J. P., Hou, S.-M., Nicklas, J. A. and Finette, B. A. (2003). "In vivo transposition mediated by V(D)J recombinase in human T lymphocytes." The EMBO Journal 22(6): 1381-1388. (PubMed | DOI | Journal | Google Scholar)

Messier and coworkers show that in human T lymphocytes, the excised DNA fragments from VDJ recombination can be reintegrated in genomic DNA, in this case causing disruption of the gene for a metabolic enzyme. Like Clathworthy et al (2003, in this bibliography), this paper provides strong evidence for a role of RAG1/2 as a functional transposase.

Cannon, J. P., Haire, R. N., Rast, J. P. and Litman, G. W. (2004). "The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms." Immunological Reviews 200(1): 12-22. (PubMed | DOI | Journal | Google Scholar)

Detailed review of the origin of adaptive immunity. It takes the transposon hypothesis for granted and deals mostly with the "setting" for the transposon insertion -- the ancestral receptors and cells, etc.
"A mechanism that most likely gave rise to the adaptive immune system has been identified (1, 2) and is discussed elsewhere in the text. However, to understand the evolution of vertebrate adaptive immunity in detail, the characteristics of the immune systems of pre-adaptive ancestors must be reconstructed.

[...]

1. Agrawal A, Eastman QM, Schatz DG. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 1998;394: 744-751.

2. Hiom K, Melek M, Gellert M. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 1998;94:463-470." (pp. 12-13, 21)

Davis, M. M. (2004). "The evolutionary and structural 'logic' of antigen receptor diversity." Seminars in Immunology 16: 239-243. (PubMed | DOI | Journal | Google Scholar)

Article on the evolutionary advantages of immune system receptor diversity. Highly technical.

Eason, D. D., Cannon, J. P., Haire, R. N., Rast, J. P., Ostrov, D. A. and Litman, G. W. (2004). "Mechanisms of antigen receptor evolution." Seminars in Immunology 16: 215-226. (PubMed | DOI | Journal | Google Scholar)

Detailed review of the evolutionary origin of adaptive receptors. All of the figures are useful summaries of various points.

The basic conclusion is that while the exact ancestral (pre-rearranging) receptor has not been found, many close relatives sharing key properties have been discovered.
"Taken together, the results suggest that the adaptive immune system in vertebrates may have been derived in unique ways from different sets of 'primordial' receptors, of which one gave rise to the Ig/TCR, another generated the VLRs, and other receptors provided protective immunity in invertebrates and protochordates, further blurring distinctions between the traditional views of adaptive and innate immunity." (pp. 224-225)

Flajnik, M. F. and Du Pasquier, L. (2004). "Evolution of innate and adaptive immunity: can we draw a line?" Trends in Immunology 25(12): 640-644. (PubMed | DOI | Journal | Google Scholar)

New developments in the study of the evolution of adaptive immunity, especially noting that the lines between "innate" and "adaptive" immunity are becoming blurred as more organisms are studied. Representative quotes:
"Particularly exciting are the discoveries of a new gene rearrangement mechanism in lampreys and a somatic diversification of mollusk immune genes." (p. 640)

"For comparative immunologists, these new sequencing data have turned us into kids in a candy shop and have spawned new insights into the integration of different immune systems." (p. 640)

"The birth of the adaptive immune system is believed to have occurred when an Ig superfamily (Igsf) gene of the variable (V) type was invaded by a transposable element containing RAG1 and RAG2 genes [5,6]. This innovative event, which greatly augmented receptor diversity (and heightened the risk of autoimmunity), must have been crucial for the adaptive immune system, even if it were not truly the initiating event [7] because all of the antigen receptor loci rearrange in a similar fashion (see later). There are several invertebrate Igsf family members having features of Ig or TCR V genes, which could be related to the ancestral gene invaded by the transposon [8-10]." (p. 640, emphases original)

"Already, other V genes with features similar to Ig or the TCR and potentially related to the ancestral Igsf gene invaded by the transposon have been isolated...." (p. 641)

"Every immunology student is taught that the jawed-vertebrate adaptive immune system was grafted onto the innate system, co-opting pre-existing effector mechanisms of defense [27]." (p. 643)

[References]

1 Medzhitov, R. et al. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397

2 Hoffmann, J.A. and Reichhart, J.M. (2002) Drosophila innate immunity: an evolutionary perspective. Nat. Immunol. 3, 121-126

3 G. Koretsky (ed. in chief) (2004) Primitive Immune Systems. (J.A. Hoffman, ed.) Immunol. Rev. 198, 303

4 Flajnik, M.F. et al. (2003) Evolution of the immune system. In Fundamental Immunology (Paul, W.E. ed.), pp. 519-570, Lippincott, Williams & Wilkins, Philadelphia

5 Bernstein, R.M. et al. (1996) Primordial emergence of the recombination activating gene 1 (RAG1): sequence of the complete shark gene indicates homology to microbial integrases. Proc. Natl. Acad. Sci. U. S. A. 93, 9454-9459

6 Agrawal, A. et al. (1998) Transposition mediated by RAG1 and RAG and its implications for the evolution of the immune system. Nature 394, 744-751

7 Erwin, D.H. and Krakauer, D.C. (2004) Evolution. Insights into innovation. Science 304, 1117-1119

8 Azumi, K. et al. (2003) Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: "waiting for Godot". Immunogenetics 55, 570-581

9 Du Pasquier, L. et al. (2004) Immunoglobulin superfamily receptors in protochordates: before RAG time. Immunol. Rev. 198, 233-248

10 Van den Berg, T.K. et al. (2004) On the origins of adaptive immunity: innate immune receptors join the tale. Trends Immunol. 25, 11-16

Galaktionov, V. G. (2004). "Evolutionary Development of the Immunoglobulin Family." Biology Bulletin 31(2): 101-111. (PubMed | DOI | Journal | Google Scholar)

Reviews the evolutionary origin of immunoglobulins, particularly how the immunoglobulin domain has been reused in many different receptors.
"It is believed that RAG was originally introduced by a retrovirus into the genome of ancestral vertebrates, specifically, into the region occupied by the single V gene." (p. 110)

Gould, S. J., Hildreth, J. E. and Booth, A. M. (2004). "The evolution of alloimmunity and the genesis of adaptive immunity." Quarterly Review of Biology 79(4): 359-382. (PubMed | DOI | Journal | Google Scholar)

A long review article in the prestigious general biology journal Quarterly Review of Biology. Stephen J. Gould (a different one than the famous paleontologist) argues that alloimmunity (recognition of self vs. nonself) evolved first, allowing the slightly later evolution of the hypervariable adaptive immune system (the variability creates the risk of accidentally attacking self-cells, so preexisting alloimmunity would ameliorate this).
"Given that alloimmunity arose more than 550 million years ago, at the dawn of animal evolution, and that adaptive immunity arose approximately 100 million years later at the origin of the jawed vertebrates (Schatz 1999), the most parsimonious explanation for why the two systems share so many features is that adaptive immunity evolved from a preexisting alloimmune system. We propose that hypervariable alloimmunity was exapted for adaptive immune responses soon after its genesis, an evolutionary event that could be selected by virtually any pathogen, even HAAPs." (p. 373)

Holmes, E. C. (2004). "Adaptation and Immunity." PLoS Biology 2(9): 1269-1269. (PubMed | DOI | Journal | Google Scholar)

This short primer article in PLoS Biology discusses the well-known adaptive value of having diverse antigen receptor genes, and the evolutionary arms race between immune system cells attempting to detect pathogens, and the pathogens attempting to avoid detection.
"It is therefore little wonder that the host and pathogen genes that control infection and immunity frequently show high levels of genetic diversity and present some of the best examples of positive selection (adaptive evolution) reported to date (Yang and Bilawski 2000). In particular, rates of nonsynonymous substitution per site (resulting in an amino acid change; dN) often greatly exceed those of synonymous substitution per site (silent change; dS), as expected if most mutations are fixed becuase they increase fitness." (p. 1267)

[Reference]

Yang Z, Bielawski JP (2000) Statistical methods for detecting molecular adaptation. Trends Ecol Evol 15: 496-502.

Jones, J. M. (2004). "The taming of a transposon: V(D)J recombination and the immune system." Immunological Reviews 200(1): 233-248. (PubMed | DOI | Journal | Google Scholar)

Review exploring the diversity of transposon systems and their relationship to V(D)J recombination.
"The study of V(D)J recombination has been continually informed by research into other systems, and it is now apparent that V(D)J recombination shares a particularly close relationship with the family of transposons that includes Ac/Ds. These similarities support the hypothesis that V(D)J recombination evolved from a primordial transposon." (pp. 233-234)

Nonaka, M. and Yoshizaki, F. (2004). "Evolution of the Complement System." Molecular Immunology 40(12): 897-902. (PubMed | DOI | Journal | Google Scholar)

Technical review of the origin of the innate (non-adaptive) immune system.
"Here, we discuss an early evolution of the complement components, both the non-modular C3 family and the other modular components, revealed by recent molecular analysis of possible complement genes from [a] variety of animals and the recently published genome analysis of an ascidian, [a tunicate or sea squirt], Ciona intestinalis." (p. 897)

"Thus, the evolution of the vertebrate complement system could be accomplished by integration of several independent functional units into a single reaction system through making a functional linkage among them." (p. 901)

Pancer, Z., Amemiya, C. T., Ehrhardt, G. R. A., Ceitlin, J., Gartland, G. L. and Cooper, M. D. (2004). "Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey." Nature 430(6996): 174-180. (PubMed | DOI | Journal | Google Scholar)

Evidence of a different system of adaptive immunity in an early-diverging vertebrate, the sea lamprey.
"Different evolutionary strategies were thus used to generate highly diverse lymphocyte receptors through rearrangement of LRR modules in agnathans (jawless fish) and of immunoglobulin gene segments in gnathostomes (jawed vertebrates)." (p. 174)

Rothenberg, E. V. and Pant, R. (2004). "Origins of lymphocyte developmental programs: transcription factor evidence." Seminars in Immunology 16(4): 227-238. (PubMed | DOI | Journal | Google Scholar)

Origins of lymphocytes (vertebrate immune system cells). Highly technical.

Cooption reference:
"Co-option of group C factors from other ancestral roles appears to have been harnessed for control of TCR and Ig gene rearrangement and expression." (p. 234)

"The evidence we have reviewed indicates that the full range of different transcription factor types needed to make lymphocytes were available in the genome at least as early as the emergence of urochordates (e.g., ascidians). In other words, the existence of transcription factors of these general families was not the rate-limiting feature for the evolution of lymphocyte development." (p. 234)

Schatz, D. G. (2004). "Antigen receptor genes and the evolution of a recombinase." Seminars in Immunology 16(4): 245-256. (PubMed | DOI | Journal | Google Scholar)

Reviews the transposon hypothesis for the origin of rearranging receptors. Fig. 3 (p. 250) gives the RAG transposon model. The evidence is also reviewed in detail on p. 250.

The authors make an interesting prediction:
"Hence, one might expect to find in the genome of vertebrates relics of these other jumps, including degenerate versions of pairs of RSSs or of the RAG open reading frames." (p. 251)

Stavnezer, J. and Amemiya, C. T. (2004). "Evolution of isotype switching." Seminars in Immunology 16(4): 257-275. (PubMed | DOI | Journal | Google Scholar)

Long, technical review of the evolution of an aspect of the adaptive immune system (CSR, class switch recombination) apparently restricted to tetrapods (amphibians, reptiles, mammals, birds).
"This chapter will review the evolution of the ability to express antibodies, or immunoglobulins (Igs) of different classes or isotypes." (p. 257)
Figure on p. 258 shows diversity of immune system gene organization.

Zhou, L., Mitra, R., Atkinson, P. W., Hickman, A. B., Dyda, F. and Craig, N. L. (2004). "Transposition of hAT elements links transposable elements and V(D)J recombination." Nature 432: 995-1001. (PubMed | DOI | Journal | Google Scholar)

Discovery of a transposon with mechanistic and sequence similarities to the RAG genes.
"It had been suggested that the V(D)J recombination system may have evolved from an ancient transposable DNA element12, 50. Our findings here of such a close mechanistic relationship between hAT transposition and V(D)J recombination...and the related active sites of hAT tranposases and RAG1 provides strong support for the view that V(D)J recombination evolved from transposable elements." (p. 1000)

[References]

12. Gellert, M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annu. Rev. Biochem. 71, 101-132 (2002).

18. Hiom, K., Melek, M. & Gellert, M. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94, 463-470 (1998).

19. Agrawal, A., Eastman, O. M. & Schatz, D. G. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394, 744-751 (1998).

20. van Gent, D. C., Mizuuchi, K. & Gellert, M. Similarities between initiation of V(D)J recombination and retroviral integration. Science 271, 1592-1594 (1996).

50. Lewis, S. M. & Wu, G. E. The origins of V(D)J recombination. Cell 88, 159-162 (1997).

Klein, J. and Nikolaidis, N. (2005). "The descent of the antibody-based immune system by gradual evolution." Proceedings of the National Academy of Sciences 102(1): 169-174. (PubMed | DOI | Journal | Google Scholar)

Argues against the "big bang" model of immune system evolution which asserts that the main features of the immune system came together "suddenly", i.e., in less than 50 million years. Instead, it argues that the processes was more graduated and step-by-step. Given that the research community seems to agree that the introduction of RAG clearly was a key step and would be "sudden" compared to other forms of genetic change, but also agrees that many other more common evolutionary processes and precursors were also involved in the origin of adaptive immunity, it can be argued that debating the "big bang" label is not particularly illuminating. Regardless, in doing so Klein and Nikolaidis re-emphasize some useful points:
"We argue that the AIS [Antibody-based Immune System] has been assembled from elements that have primarily evolved to serve other functions and incorporated existing molecular cascades, resulting in the appearance of new organs and new types of cells." (p. 169)

"In reality, however, the AIS is an example of an organ system that has evolved gradually through a series of small steps over an extended period." (p. 169)
Figure 2 shows how many organisms lack many of the parts found in the most sophisticated systems.

Cannon, J. P., Haire, R. N., Pancer, Z., Mueller, M. G., Skapura, D., Cooper, M. D. and Litman, G. W. (2005). "Variable Domains and a VpreB-like molecule are present in a jawless vertebrate." Immunogenetics 56(12): 924-929. (PubMed | DOI | Journal | Google Scholar)

This paper describes a family of non-rearranging receptors in sea lampreys that are closely related to modern immunoglobulins and, together with papers by Cannon et al (2002, in this bibliography) and Suzuki et al (2005, Journal of Immunology, 174:2885-91) constitutes strong evidence of the existence of multiple, diverse families of immunoglobulin-like proteins predating the rearranging antigen receptors found in jawed vertebrates.
"This is the first indication of a molecule related to the B cell receptor (BCR) complex in a species that diverged prior to the jawed vertebrates in which RAG-mediated adaptive immunity is first encountered." (p. 924)

Kapitonov, V. V. and Jurka, J. (2005). "RAG1 Core and V(D)J Recombination Signal Sequences Were Derived from Transib Transposons." Public Library of Science Biology 3(6): e181:0001-0014. (PubMed | DOI | Journal | Google Scholar)

Reports the discovery of homologs of RAG1 in several non-chordate phyla -- this is the direct evidence of a free-living transposon suggested by Lewis in 1999. The summary figure was used by Ken Miller during his trial testimony.
"Even prior to the discovery of RAG1 and RAG2, it had been suggested that the first two RSSs were originally terminal inverted repeats (TIRs) of an ancient transposon whose accidental insertion into a gene ancestral to BCR and TCR, followed by gene duplications, triggered the emergence of the V(D)J machinery [4]. Later, this model was expanded by the suggestion that both RAG1 and RAG2 might have evolved from a transposase (TPase) that catalyzed transpositions of ancient transposons flanked by TIRs that were precursors of RSSs [9]. This model has received additional support through observations of similar biochemical reactions in transposition and V(D)J recombination [10,11]. Finally, it was demonstrated that RAG1/2 catalyzed transpositions of a DNA segment flanked by RSS12 and RSS23 in vitro [12,13] and in vivo in yeast [14]. In vertebrates, in vivo RAG-mediated transpositions are strongly suppressed, probably to minimize potential harm to genome function. So far, only one putative instance of such a transposition has been reported [15]. However, given the lack of significant structural similarities between RAGs and known TPases, the "RAG transposon" model [9,12,13,16] remained unproven. Here we demonstrate that the RAG1 core and RSSs were derived from a TPase and TIRs encoded by ancient DNA transposons from the Transib superfamily [17]." (pp. e181-e182)

[References]
4. Sakano H, Huppi K, Heinrich G, Tonegawa S (1979) Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 280: 288-294.

[...]

9. Thompson CB (1995) New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3: 531-539.

10. van Gent DC, Mizuuchi K, Gellert M (1996) Similarities between initiation of V(D)J recombination and retroviral integration. Science 271: 1592-1594.

11. Melek M, Gellert M, van Gent DC (1998) Rejoining of DNA by the RAG1 and RAG2 proteins. Science 280: 301-303.

12. Agrawal A, Eastman QM, Schatz DG (1998) Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394: 744-751.

13. Hiom K, Melek M, Gellert M (1998) DNA transposition by the RAG1 and RAG2 proteins: A possible source of oncogenic translocations. Cell 94: 463-470.

14. Clatworthy AE, Valencia MA, Haber JE, Oettinger MA (2003) V(D)J recombination and RAG-mediated transposition in yeast. Mol Cell 12: 489-499.

15. Messier TL, O'Neill JP, Hou SM, Nicklas JA, Finette BA (2003) In vivo transposition mediated by V(D)J recombinase in human T lymphocytes. EMBO J 22: 1381-1388.

16. Lewis SM, Wu GE (2000) The old and the restless. J Exp Med 191: 1631-1636.

17. Kapitonov VV, Jurka J (2003) Molecular paleontology of transposable elements in the Drosophila melanogaster genome. Proc Natl Acad Sci U S A 100: 6569-6574.

Du Pasquier, L. (2005). "Meeting the demand for innate and adaptive immunities during evolution." Scandinavian Journal of Immunology 62(s1): 39-48. (PubMed | DOI | Journal | Google Scholar)

Detailed review of the total immune responses across metazoa, focusing on the demands imposed by natural selection, and the evolution of cooperation between adaptive and nonadaptive systems.
"Immunoglobulins and T-cell receptors

The RAG1 and 2 complexes looked so far like the only new component responsible for the adaptive system of vertebrates because no related genes were found in invertebrates. However, the discovery of a RAG2-like product with homologs among metazoa and plants (called 'peas' and showing the same composition in 'kelch' domains as RAG2) and associated with the meiotic chromatin, may force us to revise the hypothesis of a RAG transfer by transposition in the immediate ancestors of gnathostomes [32]. What is in question is perhaps not the transposing-like feature of this enzymatic system but the way it was involved in immunity and its association with RAG1. Could have the lymphocyte RAG2 arisen by duplication of a 'peas'-like gene at the time of genome duplications? Maybe the introduction of RAG1 of which [a] homolog can now be found in Echinoderms [33] was the key step for the adaptive system." (p. 44)

"In the Introduction, the simultaneity and the diversity of the pressures that led to the development of immunity at the beginning of the existence of metazoa were stressed. As a result, independent pathways of immunity functioning on different principles of recognition developed, probably in parallel, each being pushed for diversification during adaptation to the changing environment. Some organisms trusted conservatively the genes devoted to their immune system; other added and allowed some randomness in their expression. In the comparative studies one has observed convergences, mimicry, duplications, dead ends, complementation or even perhaps competitions, with a trend towards individualization of responses to the point where the distinctions between adaptive and innate immunity are uncertain. The diversification of the immune molecules has made the necessary control of their expression a difficult task, demanding the involvement of many other gene families that were recruited alongside in the build up of the integrated immune systems. The individual defense mechanisms do not work in isolation in any organism but instead are part of a coherent whole. In fact, there are many unknown genes expressed during immune responses of the simplest organisms outside vertebrates [54]. In addition to the now more fashionable protochordates and jaw-less vertebrates, it would be important to include the study of arthropods less derived than Drosophila such as the horseshoe crab. One should also include the Cnidaria whose genes’ sequences are surprisingly close to those of deuterostomes and the genome of which could contain a reservoir of interesting information for the immunologist preoccupied with evolutionary issues [55]. In those organisms, examination of the genome and individual studies of the regulations and interactions of the different components of their immune systems may provide information as to how to handle the dysfunctions of what I foolishly dared to call in the introduction our ideal Homo sapiens immune system." (p. 47)

[References]

32 Ohinata Y, Sutou S, Mitsui Y. A novel testis-specific RAG2-like protein, Peas: its expression in pachytene spermatocyte cytoplasm and meiotic chromatin. FEBS Lett 2003;537:1-5.

33 Cannon JP, Haire RN, Rast JP, Litman GW. The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms. Immunol Rev 2004;200:12-22.

54 De Gregorio E, Spellman PT, Rubin GM, Lemaitre B. Genomewide analysis of the Drosophila immune response by using oligonucleotide microarrays. Proc Natl Acad Sci USA 2001;98:12590-5.

55 Galliot B, Schmid V. Cnidarians as a model system for understanding evolution and regeneration. Int J Dev Biol 2002;46 (1 Spec No): 39-48.

Janssen, B. J. C., Huizinga1, E. G., Raaijmakers, H. C. A., Roos, A., Daha, M. R., Nilsson-Ekdahl, K., Nilsson, B. and Gros, P. (2005). "Structures of complement component C3 provide insights into the function and evolution of immunity." Nature 437(7058): 505-511. (PubMed | DOI | Journal | Google Scholar)

The authors report the crystal structure of the key innate immunity protein, C3, and deduce certain features of the evolutionary origin of the protein, such as internal domain duplications. This research came out the week before trial and was cited in Kenneth Miller's direct testimony.

Cohn, M. (2006). "What are the commonalities governing the behavior of humoral immune recognitive repertoires?" Developmental and Comparative Immunology 30(1-2): 19-42. (PubMed | DOI | Journal | Google Scholar)

Long review of selection-related issues in the evolution of immunity.
"The evolution of the immune system has been reviewed over the years from several points of view [1-10]. I will try to take a different tack by stressing selectable function rather than structure, genealogy, sequence, homology, gene dynamics, etc., the basic tools of comparative immunologists. This is not to downplay the importance of these analyses, which are, in fact, fundamental and indispensable, but rather to see whether another approach will confirm our present views or, hopefully, give us new insights." (p. 19)

[References]

[1] Du Pasquier L, Flajnik M. Origin and evolution of the vertebrate immune system. In: Paul WE, editor. Fundamental immunology. Philadelphia, PA: Lippincott-Raven Publishers; 1999. p. 605-50.

[2] Diaz M, Flajnik MF. Evolution of somatic hypermutation and gene conversion in adaptive immunity. Immunol Rev 1998; 162:13-24.

[3] Butler JE. Immunoglobulin gene organization and the mechanism of repertoire development. Scand J Immunol 1997;45:455-62.

[4] Du Pasquier L, Wilson M, Greenberg AS, Flajnik MF. Somatic mutation in ectothermic vertebrates: Musings on selection and origins. Curr Topics Microbiol Immunol 1998; 229:199-216.

[5] Flajnik M, Rumfelt LL. Early and natural antibodies in nonmammalian vertebrates. Curr Topics Microbiol Immunol 2000;252:233-40.

[6] Litman GW, Anderson MK, Rast JP. Evolution of antigen binding receptors. Annu Rev Immunol 1999;17:109-47.

[7] Immune systems of ectothermic vertebrates. In: Parham P, editor. Immunological reviews, 1998. p. 166-384.

[8] Flajnik M. Comparative analysis of immunoglobulin genes: Surprises and portents. Nat Rev Immunol 2002;2:688-98.

[9] Marchalonis JJ, Jensen I, Schuluter SF. Structural, antigenic and evolutionary analyses of immunoglobulins and T cell receptors. J Mol Recogn 2002;15:260-71.

[10] Neuberger MS. Antibodies: a paradigm for the evolution of molecular recognition. Biochem Soc Trans 2002;30:341-50.

Marchalonis, J. J., Adelman, M. K., Schluter, S. F. and Ramsland, P. A. (2006). "The antibody repertoire in evolution: Chance, selection, and continuity." Developmental and Comparative Immunology 30(1-2): 223-247. (PubMed | DOI | Journal | Google Scholar)

Massive review with 177 references. Deals with mutation and selection explicitly.
"At the onset, we emphasize that evolution is a stochastic or accidental process building upon the spontaneous generation of mutations followed by natural selection based upon survival to reproduce under external/environmental conditions." (p. 224)

"It has been proposed that the rapid evolutionary emergence of the combinatorial response was catalyzed by the horizontal transfer of RAG genes to an ancestral vertebrate [22-26]. The prokaryotic origin of these genes is buttressed by the lack of introns and by homology to microbial site-specific recombinases [23,27-29]." (p. 224)

[References]

[22] Bartl S, Baltimore D, Weissman IL. Molecular evolution of the vertebrate immune system. Proc Natl Acad Sci USA 1994;91:10769-70.

[23] Bernstein RM, Schluter SF, Bernstein H, Marchalonis JJ. Primordial emergence of the recombination activating gene 1 (RAG1): sequence of the complete shark gene indicates homology to microbial integrases. Proc Natl Acad Sci USA 1996;93:9454-9.

[24] Schluter SF, Bernstein RM, Bernstein H, Marchalonis JJ. ‘Big Bang‘ emergence of the combinatorial immune system. Dev Comp Immunol 1999;23:107-11.

[25] Laird D, De Tomaso A, Cooper MD, Weissman I. 50 million years of chordate evolution: seeking the origins of adaptive immunity. Proc Natl Acad Sci USA 2000;97:6924-6.

[26] Plasterk R. V(D)J recombination. Ragtime jumping. Nature 1998;394:718-9.

[27] Banerjee-Basu S, Baxevanis AD. The DNA-binding region of RAG1 is not a homoeodomain. Genome Biol 2002;3:1004.

[28] Schatz DG. Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system. Immunol Res 1999;19:169-82.

[29] Agrawal A, Eastman QM, Schatz DG. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 1998;394:744-51.

Acknowledgements

Thanks to Andrea Bottaro, Matt Inlay, and the Panda's Thumb crew for suggestions and corrections. Any mistakes that remain are my own.

Unannotated Bibliography on the Evolutionary Origin of the Immune System

by Nick Matzke

Sections:
Introduction
How the list was assembled
Quantitative Description
By Year
By Author
By Journal
The Implications
Full Bibliography: Alphabetical
Full Bibliography: Chronological
Acknowledgements

Introduction

This webpage contains contains a bibliography of 357 references specifically on the evolutionary origin of the immune system. This list includes the 70 or so references in the annotated bibliography and several hundred additional articles (and a few more books and book chapters). The purpose of this list is to demonstrate that the shorter list is just a sample of what is in the literature. Some simple statistics will also be used to describe the collection.

How the list was assembled

This list was assembled over several months. Beginning with the annotated bibliography, articles were added to this collection if they were cited an informative way in an article in the evolutionary immunology literature, and if they appeared to be directly on or directly relevant to the evolutionary origins of immune systems. For example, Hiom et al. (1998), unintentionally neglected in the annotated bibliography, is repeatedly referenced in the evolutionary immunology literature. Other articles were included as they were gradually discovered in reference lists and database searches, based on an inspection of the title and/or abstract.

The references that were collected fell into several main groups:

  1. Articles published after the Kitzmiller case
  2. Articles repeatedly referenced by immunologists in the annotated bibliography
  3. Articles by noted evolutionary immunologists that had evolutionary content upon inspection
  4. Articles picked up in "Related Articles" searches on PubMed, starting with articles in the annotated bibliography
  5. A few relevant books and book chapters that were discovered or rediscovered after the annotated bibliography was assembled
Many of the articles in this collection have not been looked up, but the chances of "false positives" should be quite low, as the evolutionary relevance is usually made clear by the title and abstract, or by repeated citation in the literature.

Although this list of publications is much longer, it still cannot be considered complete or representative of the field. Many biases are identifiable:

  1. The collection is still biased towards adaptive immunity and V(D)J recombination, although a great deal more comparative immunology has been included.
  2. The collection is biased towards authors found in the annotated bibliography.
  3. The collection exhibits a "pull of the recent", as recent articles are more likely to be accessible, more likely to be cited, and more likely to be listed in online databases.
  4. Like the annotated bibliography, this collection is biased towards review literature rather than research literature.

Nevertheless, some interesting features emerge when the bibliography is analyzed quantitatively. In 1996, Michael Behe claimed that a thorough search of the scientific literature showed that the evolutionary emperor had no clothes. About the evolution of irreducibly complex systems in general, Behe wrote,
There is no publication in the scientific literature -- in prestigious journals, specialty journals, or books -- that describes how molecular evolution of any real, complex, biochemical system either did occur or even might have occurred." (Darwin's Black Box, p. 185)
This was in a chapter boldly entitled "Publish or Perish," which contains section headings like "The Missing Papers" and "Searching High and Low." Behe made a great show of searching biochemistry textbooks, the university library, and the journals, especially a detailed search through the Journal of Molecular Evolution, which occupies four pages of Darwin's Black Box (pp. 173-177). On p. 179, Behe wrote,
The search can be extended, but the results are the same. There has never been a meeting, or a book, or a paper on the details of the evolution of complex biochemical systems."
Behe's famous assertions about the evolutionary immune system literature were quoted in the annotated bibliography, but it is also worth noting that Behe cited a grand total of five publications on evolutionary immunology in the entire immune system chapter of Darwin's Black Box. They have been marked with an asterisk (*) for the reader's convenience. In his new afterword to the tenth anniversiary edition of Darwin's Black Box, Behe cited exactly one additional immune system paper, Klein and Nikolaidis (2005), also marked with an asterisk in this list. Behe completely misses the point of the article, which is discussed in the annotated bibliography. Behe's critique consists of, first, trumpeting the mere fact that the the authors use words like "probably", as if such qualifiers were not found in virtually every careful scientific publication. Apart from Behe, this juvenile tactic is only commonly found among the least sophisticated internet creationists. Second, Behe doesn't find enough mentions of the words he thinks he should find, cognates of "Darwin", "natural selection", and "mutation" -- Behe made this same trivial critique of several immune system articles at trial, and the problems with it were exposed in short order during Rothschild's cross-examination. Here, we can add that Behe's problem is that the immune system literature is too advanced for him -- general "mutations" are not discussed so much as the specific kinds of mutations relevant to the origin of the immune system, such as -- wait for it -- transposition. Regarding natural selection, entire articles, indeed entire careers (see articles by Cohn, Gould, etc.) have been devoted to studying, and often mathematically modeling, the selection forces that lead to immune systems, the diversity of immune system receptor genes, and the ways that various specific hypotheses can be tested by examining substitution ratios and other evidence. Behe seems to assume that if the first random article he reads doesn't start completely from scratch and educate him personally about everything going on in research labs across the country, then the article is worthless. The reality, on the other hand, is that any article specifically focusing on natural selection and the immune system, that didn't reach the level of sophistication of Cohn's work, wouldn't even be worth publishing.

Finally, Behe says that Klein and Nikolaidis admit themselves that this immune system evolution stuff is just speculation, because they suggest some experiments that have not yet been done, and without them "their scenario would 'remain hopelessly in the realm of mere speculations.'" But let's look at the actual concluding paragraph of the article:
The agnathan [jawless fish] genomes should bear witness to how close they have come to acquiring the AIS [Adaptive Immune System]. The closeness can be determined experimentally in two ways: by introducing agnathan genes into the gnathostome [jawed vertebrate] genome or the other way around. It should be possible to determine which changes are necessary for agnathan genes, such as the PSMB, ATP-binding cassette transporter, or CD45, to replace the functions of their gnathostome counterparts. In the opposite direction, introducing gnathostome genes such MHC, BCR, or RAG, into agnathan cells or animals should reveal to what extent the cells' or animals' physiology is "ready" for some of the functions associated with the AIS. Extant agnathans are, of course, evolutionarily far away from the agnathan-gnathostome ancestors, but this kind of experimental molecular evolution should nevertheless shed light on events that would otherwise remain hopelessly in the realm of mere speculations. (Klein and Nikolaidis, 2005, p. 174)
In context, it is clear that what the authors consider "speculation" is the detail of exactly how close the agnathan genome is to acquiring an adaptive immune system. In figure 2, the authors show that agnathans, which lack the adaptive immune system, nevertheless have 12 of the 16 key components of adaptive immunity that the authors identify, and in the conclusion the authors are simply wondering what would happen if a few more key components of the adaptive immune system were introduced into agnathans. Strangely, Behe doesn't take the time to explain how the "partial" adaptive immune system of agnathans remains functional in the light of his famous claim than "any precursor to an irreducibly complex system that is missing a part is by definition nonfunctional" and therefore "cannot be produced gradually" because "it would have to arise as an integrated unit, in one fell swoop, for natural selection to have anything to act on" (Behe 1996, p. 39).

Regardless, Behe writes on p. 270 of his afterword,
Today the situation remains unchanged from what it was ten years ago. As I wrote in Chapter 8:
There is no publication in the scientific literature -- in prestigious journals, specialty journals, or books -- that describes how molecular evolution of any real, complex, biochemical system either did occur or even might have occurred. There are assertions that such evolution occurred, but absolutely none are supported by pertinent experiments or calculations.
(Behe 2006, p. 270)
With this in mind, let us examine the bibliography.


Quantitative Description

This bibliography contains 357 articles, books, and book chapters. Counting up the page numbers in the citations yields about 4,700 pages of material, not including the books which would total another few thousand pages. The citations have been arranged chronologically and alphabetically.

By Year

The number of articles in the bibliography published in each year since 1962 is plotted in the below graph. The number for 2006 was estimated by multiplying by three the number of articles available as of April 2006.

Number of publications per year found in this bibliography. Keeping in mind that the bibliography is probably biased against older articles, the general trend is still suggestive of a rapidly growing research field. The vertical dotted line represents the publication of Behe's 1996 book Darwin's Black Box
The bibliography was divided into two periods, the 34 year period from 1962-1995, and the 11 year period from 1996-2006. Darwin's Black Box was published in early 1996, and it can be seen that this bibliography contains 150 articles on evolutionary immunology published before that date. This is 39% of the collection. This seems to substantially weaken Behe's 1996 claims about the scientific literature. From 1996-2006, a further 236 articles were published, or 61% of the collection. This seems to contradict Behe's re-assertions of his claims in the 2006 edition of Darwin's Black Box.

By Author

The authorship of the articles can also be quantified. Academics know that every academic has a specialty, and that in order to be conversant in a particular field you simply must be familiar with the research and publications of the key people in that subfield. This bibliography contains 192 different first authors, and hundreds of additional secondary authors. Who are some of the leaders in evolutionary immunology? The top ten first authors in the bibliography are listed below, along with the number of times each of these researchers appears as an author anywhere in an article authorship list:

AuthorNo. articles
(first author)
No. articles
(any author)
Gary Litman2249
John Marchalonis2138
Martin Flajnik1323
Louis Du Pasquier1219
Masaru Nonaka1122
L. William Clem714
Sir Frank Macfarlane Burnet66
David Schatz59
J. Oriol Sunyer57
Melvin Cohn46
The top ten first authors in the bibliography. The number of publications in the bibliography that they have first-authored, or coauthored in any fashion, is listed. All of these authors have written many more articles than just the ones listed here; see their linked webpages for publication lists and research descriptions. E.g., Martin Flajnik, "My work is centered on the evolution of the immune system, with the major goal being to understand the origins of adaptive immunity...."
Although the top ten authors constitute only 5.2% of the first authors in this bibliography, they have first-authored 106 (30%) of the articles. Counting articles on which the top ten have been an author in any position, including first, they have coauthored over half of the articles in the bibliography (193, or 52%).

At this juncture, readers should ask themselves: has the ID movement grappled with the work of any of these researchers? Is the ID movement simply hoping that they can keep their supporters ignorant that numerous researchers are, daily, doing the work that the ID movement says doesn't exist? If the reader has followed the "intelligent design" movement for a substantial length of time, but has never heard of these researchers or their work, they should ask themselves if they have ever had a realistic picture of what is actually going on in the scientific community.

By Journal

The top ten journals in the bibliography can be tabulated in a similar fashion:

JournalNo. articles
Proceedings of the National Academy of Sciences27
Developmental and Comparative Immunology25
Immunological Reviews23
Journal of Immunology21
Nature20
Cell12
Journal of Experimental Medicine10
Immunogenetics9
Molecular Immunology8
Science7
The top ten journals in the bibliography. The number of publications in the bibliography that they have appeared in each journal is listed. The top ten journals account for 162 articles, or 45% of the publications in the bibliography.
It is evident that the top ten journals in the list fall into two categories. First, immunology journals read by immunologists. This is not surprising, although it may surprise the reader to know that there is a whole journal devoted to comparative immunology. Of the publications listed in this bibliography, 192 (54%) are published in journals or books with a cognate of "immunity" in the title, while the rest are in a wide array of more general biology and science publications.

The second category found in the top ten list, of course, is prestigious general science journals (Nature, Science, PNAS, or the more specialized Cell, the most prestigious journal in cell biology). The ID movement would kill for just one ID publication in any one of these journals.

It is worth noting that the Journal of Molecular Evolution, the journal that Behe spent four pages of Darwin's Black Box on in a great show of allegedly sincere searching for evolution articles, has only one publication in this entire bibliography. Behe pretends that the Journal of Molecular Evolution must be the primary place one would look for the kinds of articles that he seeks -- after all, "molecular evolution" is right there in the title! But if one understands the subtleties of academic tradition, one realizes that JME has tended to focus on slightly different topics such as gene phylogenies and molecular clocks. It is not necessarily the journal one would go to for everything involving evolution for any system, especially when fields like immunology have a set of their own journals, and save the really revolutionary stuff for Science and Nature.


The Implications

In the new afterword to Darwin's Black Box, Behe told his readers what should be expected "at an absolute minimum" for research on the evolutionary origin of the eukaryotic cilium:
It would take at least as much work to figure out how such a structure could evolve by random mutation and natural selection as it did to figure out how it works in the first place. At an absolute minimum that would be expected to result in hundreds of papers -- both theoretical and experimental -- many reviews, books, meetings, and more, all devoted to the question of how such an intricate structure could have evolved in a Darwinian fashion. (Darwin's Black Box, 2006, p. 267)
Admittedly, this level of research has not been conducted on the evolutionary origin of the cilium yet. Although Behe claims the cilium is well understood because the basic mechanism of microtubule sliding is understood, it is actually still a deeply mysterious structure, fundamentally tied to the centriole and the centriole's role in mitosis. For example, scientists do not understand the actual physical mechanism that produces the famous 9+2 microtubule pattern of cilia or the similar pattern in the centriole template. It is hard to see how detailed an evolutionary account could get with such basic questions unanswered. The blatant contradiction between Behe's lax scientific standards for understanding current cell biology -- on the cilium, he basically says, "The microtubules slide past each other, what else is there to know?" -- and his ridiculous scientific standards for evolution -- basically, "Give me every single mutation and selection pressure in every lineage over the last billion years" -- will have to be explored in more detail elsewhere. Also saved for later is the question of where exactly the ID movement's hundreds of papers are that give detailed accounts of the ID explanation for the cilium, the immune system, etc.

Although there are not hundreds of papers, meetings, books, etc., on cilium evolution, the point of these webpages is -- as the reader has already guessed -- that evolutionary immunology does have this level of research behind it. Will the ID movement ever admit it, or will they just continue to brazenly dismiss the work of hundreds of scientists as "speculation"? Time will tell. In the meantime, unsupported statements about the lack of scientific literature on the evolution of irreducibly complex systems -- even statements from seemingly authoritative sources -- must be treated with skepticism (the ID movement has a small handful of quotes from respected scientists that they wield like talismans against criticism, but there is no evidence that these authorities have any particular familiarity with evolutionary immunology).


Full Bibliography: Alphabetical

1. Adelman, M. K., Schluter, S. F. and Marchalonis, J. J. (2004). "The natural antibody repertoire of sharks and humans recognizes the potential universe of antigens." Protein Journal 23(2): 103-118. (Google Scholar | PubMed)

2. Agrawal, A., Eastman, Q. M. and Schatz, D. G. (1998). "Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system." Nature 394(6695): 744-751. (Google Scholar | DOI | Journal | PubMed)

3. Alder, M. N., Rogozin, I. B., Iyer, L. M., Glazko, G. V., Cooper, M. D. and Pancer, Z. (2005). "Diversity and function of adaptive immune receptors in a jawless vertebrate." Science 310(5756): 1970-1973. (PubMed)

4. Al-Sharif, W. Z., Sunyer, J. O., Lambris, J. D. and Smith, L. C. (1998). "Sea urchin coelomocytes specifically express a homologue of the complement component C3." Journal of Immunology 160(6): 2983-2997. (PubMed)

5. Altmann, S. M., Mellon, M. T., Distel, D. L. and Kim, C. H. (2003). "Molecular and functional analysis of an interferon gene from the zebrafish, Danio rerio." Journal of Virology 77(3): 1992-2002. (PubMed)

6. Amemiya, C. T. and Litman, G. W. (1990). "Complete nucleotide sequence of an immunoglobulin heavy-chain gene and analysis of immunoglobulin gene organization in a primitive teleost species." Proceedings of the National Academy of Sciences 87(2): 811-815. (PubMed)

7. Amemiya, C. T., Ohta, Y., Litman, R. T., Rast, J. P., Haire, R. N. and Litman, G. W. (1993). "VH gene organization in a relict species, the coelacanth Latimeria chalumnae: evolutionary implications." Proceedings of the National Academy of Sciences 90(14): 6661-6665. (PubMed)

8. Anderson, M. K., Pant, R., Miracle, A. L., Sun, X., Luer, C. A., Walsh, C. J., Telfer, J. C., Litman, G. W. and Rothenberg, E. V. (2004). "Evolutionary origins of lymphocytes: ensembles of T cell and B cell transcriptional regulators in a cartilaginous fish." Journal of Immunology 172(10): 5851-5860. (PubMed)

9. Anonymous (1971). "A Wise Cell Knows Which its Parent." Nature 232(5308): 219-220. (DOI | Journal)

10. Armstrong, P. B. and Quigley, J. P. (1999). "Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system." Developmental and Comparative Immunology 23(4-5): 375-390. (PubMed)

11. Azumi, K., De Santis, R., De Tomaso, A., Rigoutsos, I., Yoshizaki, F., Pinto, M. R., Marino, R., Shida, K., Ikeda, M., Arai, M., Inoue, Y., Shimizu, T., Satoh, N., Rokhsar, D. S., Du Pasquier, L., Kasahara, M., Satake, M. and Nonaka, M. (2003). "Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: "waiting for Godot"." Immunogenetics 55(8): 570-581. (PubMed)

12. Banerjee-Basu, S. and Baxevanis, A. D. (2002). "The DNA-binding region of RAG 1 is not a homeodomain." Genome Biology 3(8): interactions1004.1001-1004.1004. (DOI | Journal | PubMed)

13. Bang, D. D., Verhage, R., Goosen, N., Brouwer, J. and van de Putte, P. (1992). "Molecular cloning of RAD16, a gene involved in differential repair in Saccharomyces cerevisiae." Nucleic Acids Research 20(15): 3925-3931. (PubMed)

14.* Bartl, S., Baltimore, D. and Weissman, I. L. (1994). "Molecular evolution of the vertebrate immune system." Proceedings of the National Academy of Sciences 91(23): 10769-10770. (Google Scholar | Journal | JSTOR | PubMed)

15. Bartl, S., Miracle, A. L., Rumfelt, L. L., Kepler, T. B., Mochon, E., Litman, G. W. and Flajnik, M. F. (2003). "Terminal deoxynucleotidyl transferases from elasmobranchs reveal structural conservation within vertebrates." Immunogenetics 55(9): 594-604. (PubMed)

16. Beck, G., Cooper, E. L., Habicht, G. S. and Marchalonis, J. J., eds. (1994). Primordial Immunity: Foundations for the Vertebrate Immune System. New York, The New York Academy of Sciences. (Library | PubMed | Publisher | Amazon | Google Print)

17. Beck, G., Ellis, T. W., Habicht, G. S., Schluter, S. F. and Marchalonis, J. J. (2002). "Evolution of the acute phase response: iron release by echinoderm (Asterias forbesi) coelomocytes, and cloning of an echinoderm ferritin molecule." Developmental and Comparative Immunology 26(1): 11-26. (PubMed)

18. Beck, G. and Habicht, G. S. (1996). "Immunity and the invertebrates." Scientific American 275(5): 60-63, 66. (Journal)

19. Belov, K., Deakin, J. E., Papenfuss, A. T., Baker, M. L., Melman, S. D., Siddle, H. V., Gouin, N., Goode, D. L., Sargeant, T. J., Robinson, M. D., Wakefield, M. J., Mahony, S., Cross, J. G., Benos, P. V., Samollow, P. B., Speed, T. P., Graves, J. A. and Miller, R. D. (2006). "Reconstructing an Ancestral Mammalian Immune Supercomplex from a Marsupial Major Histocompatibility Complex." PLoS Biology 4(3): e46. (PubMed)

20. Bernstein, R. M., Schluter, S. F., Bernstein, H. and Marchalonis, J. J. (1996). "Primordial emergence of the recombination activating gene 1 (RAG1): Sequence of the complete shark gene indicates homology to microbial integrases." Proceedings of the National Academy of Sciences 93(18): 9454-9459. (Google Scholar | Journal | JSTOR | PubMed)

21. Berstein, R. M., Schluter, S. F., Shen, S. and Marchalonis, J. J. (1996). "A new high molecular weight immunoglobulin class from the carcharhine shark: implications for the properties of the primordial immunoglobulin." Proceedings of the National Academy of Sciences 93(8): 3289-3293. (PubMed)

22. Boehm, T. (2006). "Co-evolution of a primordial peptide-presentation system and cellular immunity." Nature Reviews Immunology 6(1): 79-84. (DOI | Journal | PubMed)

23. Burnet, F. M. (1963). "The Evolution of Bodily Defence." Medical Journal of Australia 15: 817-821. (PubMed)

24. Burnet, F. M. (1968). "Evolution of the immune process in vertebrates." Nature 218(140): 426-430. (DOI | Journal | PubMed)

25. Burnet, F. M. (1969). "The evolution of adaptive immunity in vertebrates." Acta Pathologica, Microbiologica et Immunologica Scandinavica 76(1): 1-11. (PubMed)

26. Burnet, F. M. (1970). "A certain symmetry: histocompatibility antigens compared with immunocyte receptors." Nature 226(5241): 123-126. (DOI | Journal | PubMed)

27. Burnet, F. M. (1971). "Self-recognition in colonial marine forms and flowering plants in relation to the evolution of immunity." Nature 232(5308): 230-235. (Google Scholar | DOI | Journal | PubMed)

28. Burnet, F. M. (1973). "Multiple polymorphism in relation to histocompatibility antigens." Nature 245(5425): 359-361. (DOI | Journal | PubMed)

29. Butler, J. E. (1997). "Immunoglobulin gene organization and the mechanism of repertoire development." Scandinavian Journal of Immunology 45(5): 455-462. (PubMed)

30. Cannon, J. P., Haire, R. N. and Litman, G. W. (2002). "Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate." Nature Immunology 3(12): 1200-1207. (Google Scholar | DOI | Journal | PubMed)

31. Cannon, J. P., Haire, R. N., Pancer, Z., Mueller, M. G., Skapura, D., Cooper, M. D. and Litman, G. W. (2005). "Variable Domains and a VpreB-like molecule are present in a jawless vertebrate." Immunogenetics 56(12): 924-929. (Google Scholar | DOI | Journal | PubMed)

32. Cannon, J. P., Haire, R. N., Rast, J. P. and Litman, G. W. (2004). "The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms." Immunological Reviews 200(1): 12-22. (Google Scholar | DOI | Journal | PubMed)

33. Chartrand, S. L., Litman, G. W., Lapointe, N., Good, R. A. and Frommel, D. (1971). "The evolution of the immune response. 12. The immunoglobulins of the turtle. Molecular requirements for biologic activity of 5." Journal of Immunology 107(1): 1-11. (PubMed)

34. Chu, T. W., Capossela, A., Coleman, R., Goei, V. L., Nallur, G. and Gruen, J. R. (1995). "Cloning of a new "finger" protein gene (ZNF173) within the class I region of the human MHC." Genomics 29(1): 229-239. (PubMed)

35. Clatworthy, A. E., Valencia, M. A., Haber, J. E. and Oettinger, M. A. (2003). "V(D)J recombination and RAG-mediated transposition in yeast." Molecular Cell 12(2): 489-499. (Google Scholar | DOI | Journal | PubMed)

36. Clawson, C. C., Finstad, J. and Good, R. A. (1966). "Evolution of the immune response. 5. Electron microscopy of plasma cells and lymphoid tissue of the paddlefish." Laboratory Investigation; a journal of technical methods and pathology 15(12): 1830-1847. (PubMed)

37. Clem, I. W., De Boutaud, F. and Sigel, M. M. (1967). "Phylogeny of immunoglobulin structure and function. II. Immunoglobulins of the nurse shark." Journal of Immunology 99(6): 1226-1235. (PubMed)

38. Clem, L. W. (1971). "Phylogeny of immunoglobulin structure and function. IV. Immunoglobulins of the giant grouper, Epinephelus itaira." Journal of Biological Chemistry 246(1): 9-15. (PubMed)

39. Clem, L. W. and Leslie, G. A. (1982). "Phylogeny of immunoglobulin structure and function. XIV. Peptide map and amino acid composition studies of shark antibody light chains." Developmental and Comparative Immunology 6(2): 263-269. (PubMed)

40. Clem, L. W. and Leslie, G. A. (1982). "Phylogeny of immunoglobulin structure and function XV. Idiotypic analysis of shark antibodies." Developmental and Comparative Immunology 6(3): 463-472. (PubMed)

41. Clem, L. W. and McLean, W. E. (1975). "Phylogeny of immunoglobulin structure and function. VII. Monomeric and tetrameric immunoglobulins of the margate, a marine teleost fish." Immunology 29(4): 791-799. (PubMed)

42. Clem, L. W. and Small, P. A., Jr. (1967). "Phylogeny of immunoglobulin structure and function. I. Immunoglobulins of the lemon shark." Journal of Experimental Medicine 125(5): 893-920. (PubMed)

43. Clem, L. W. and Small, P. A., Jr. (1970). "Phylogeny of immunoglobulin structure and function. V. Valences and association constants of teleost antibodies to a haptenic determinant." Journal of Experimental Medicine 132(3): 385-400. (PubMed)

44. Cohn, M. (1998). "At the feet of the master: the search for universalities. Divining the evolutionary selection pressures that resulted in an immune system." Cytogenetics and Cell Genetics 80(1-4): 54-60. (DOI | Journal | PubMed)

45. Cohn, M. (2002). "The immune system: a weapon of mass destruction invented by evolution to even the odds during the war of the DNAs." Immunological Reviews 185: 24-38. (PubMed)

46. Cohn, M. (2005). "The common sense of the self-nonself discrimination." Springer Seminars in Immunopathology 27(1): 3-17. (PubMed)

47. Cohn, M. (2006). "What are the commonalities governing the behavior of humoral immune recognitive repertoires?" Developmental and Comparative Immunology 30(1-2): 19-42. (Google Scholar | DOI | Journal | PubMed)

48. Cooper, M. D. and Alder, M. N. (2006). "The Evolution of Adaptive Immune Systems." Cell 124(4): 815-822. (Google Scholar | DOI | Journal | PubMed)

49. Czompoly, T., Olasz, K., Simon, D., Nyarady, Z., Palinkas, L., Czirjak, L., Berki, T. and Nemeth, P. (2005). "A possible new bridge between innate and adaptive immunity: Are the anti-mitochondrial citrate synthase autoantibodies components of the natural antibody network?" Molecular Immunology. (PubMed)

50. Danilova, N. (2006). "The evolution of immune mechanisms." Journal of Experimental Zoology, Part B: Molecular and Developmental Evolution. (Google Scholar | DOI | Journal | PubMed)

51. Davidson, E. H. (1994). "Stepwise Evolution of Major Functional Systems in Vertebrates, Including the Immune System." Phylogenetic Perspectives in Immunity: The Insect Host Defense. Edited by J. A. Hoffman, C. A. Janeway and S. Natori. Austin, R.G. Landes Company: 133-142. (Library | Amazon | Google Print)

52. Davis, M. M. (2004). "The evolutionary and structural 'logic' of antigen receptor diversity." Seminars in Immunology 16: 239-243. (Google Scholar | DOI | Journal | PubMed)

53. De Gregorio, E., Spellman, P. T., Rubin, G. M. and Lemaitre, B. (2001). "Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays." Proceedings of the National Academy of Sciences 98(22): 12590-12595. (PubMed)

54. De Tomaso, A. W., Nyholm, S. V., Palmeri, K. J., Ishizuka, K. J., Ludington, W. B., Mitchel, K. and Weissman, I. L. (2005). "Isolation and characterization of a protochordate histocompatibility locus." Nature 438(7067): 454-459. (DOI | Journal | PubMed)

55. DeLuca, D., Warr, G. W. and Marchalonis, J. J. (1978). "Phylogenetic origins of immune recognition: lymphocyte surface immunoglobulins and antigen binding in the genus Carassius (Teleostii)." European Journal of Immunology 8(7): 525-530. (PubMed)

56. Diaz, M. and Flajnik, M. F. (1998). "Evolution of somatic hypermutation and gene conversion in adaptive immunity." Immunological Reviews 162: 13-24. (PubMed)

57. Difilippantonio, M. J., McMahan, C. J., Eastman, Q. M., Spanopoulou, E. and Schatz, D. G. (1996). "RAG1 mediates signal sequence recognition and recruitment of RAG2 in V(D)J recombination." Cell 87(2): 253-262. (PubMed)

58. Dodds, A. W. (1994). "Molecular and Phylogenetic Aspects of the Complement System." Phylogenetic Perspectives in Immunity: The Insect Host Defense. Edited by J. A. Hoffman, C. A. Janeway and S. Natori. Austin, R.G. Landes Company: 143-155. (Library | Amazon | Google Print)

59. Dodds, A. W. and Law, S. K. (1998). "The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin." Immunological Reviews 166: 15-26. (PubMed)

60. dos Remedios, N. J., Ramsland, P. A., Hook, J. W. and Raison, R. L. (1999). "Identification of a homologue of CD59 in a cyclostome: implications for the evolutionary development of the complement system." Developmental and Comparative Immunology 23(1): 1-14. (PubMed)

61. Dreyfus, D. H. (1992). "Evidence suggesting an evolutionary relationship between transposable elements and immune system recombination sequences." Molecular Immunology 29(6): 807-810. (Google Scholar | DOI | Journal | PubMed)

62. Du Pasquier, L. (1982). "Antibody diversity in lower vertebrates--why is it so restricted?" Nature 296(5855): 311-313. (PubMed)

63.* Du Pasquier, L. (1992). "Origin and evolution of the vertebrate immune system." Acta Pathologica, Microbiologica et Immunologica Scandinavica 100: 383. (Google Scholar)

64. Du Pasquier, L. (1993). "Phylogeny of B-cell development." Current Opinion in Immunology 5(2): 185-193. (PubMed)

65. Du Pasquier, L. (2000). "The Phylogenetic Origin of Antigen-Specific Receptors." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 159-185. (Library | PubMed | Amazon | Google Print)

66. Du Pasquier, L. (2001). "The immune system of invertebrates and vertebrates." Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 129(1): 1-15. (Google Scholar | DOI | Journal | PubMed)

67. Du Pasquier, L. (2002). "Several MHC-linked Ig superfamily genes have features of ancestral antigen-specific receptor genes." Current Topics in Microbiology and Immunology 266: 57-71. (PubMed)

68. Du Pasquier, L. (2004). "Speculations on the origin of the vertebrate immune system." Immunology Letters 92(1-2): 3-9. (PubMed)

69. Du Pasquier, L. (2005). "Germline and somatic diversification of immune recognition elements in Metazoa." Immunology Letters. (PubMed)

70. Du Pasquier, L. (2005). "Meeting the demand for innate and adaptive immunities during evolution." Scandinavian Journal of Immunology 62(s1): 39-48. (Google Scholar | DOI | Journal | PubMed)

71. Du Pasquier, L. and Litman, G. W., eds. (2000). Origin and Evolution of the Vertebrate Immune System. Current Topics in Microbiology and Immunology. Berlin, Springer. (Library | Publisher | Amazon | Google Print)

72. Du Pasquier, L., Wilson, M., Greenberg, A. S. and Flajnik, M. F. (1998). "Somatic mutation in ectothermic vertebrates: musings on selection and origins." Current Topics in Microbiology and Immunology 229: 199-216. (PubMed)

73. Du Pasquier, L., Zucchetti, I. and De Santis, R. (2004). "Immunoglobulin superfamily receptors in protochordates: before RAG time." Immunological Reviews 198: 233-248. (PubMed)

74. Dunne, D. W. and Cooke, A. (2005). "A worm's eye view of the immune system: consequences for evolution of human autoimmune disease." Nature Reviews Immunology 5(5): 420-426. (PubMed)

75. Eason, D. D., Cannon, J. P., Haire, R. N., Rast, J. P., Ostrov, D. A. and Litman, G. W. (2004). "Mechanisms of antigen receptor evolution." Seminars in Immunology 16: 215-226. (Google Scholar | DOI | Journal | PubMed)

76.* Farries, T. C. and Atkinson, J. P. (1991). "Evolution of the complement system." Immunology Today 12(9): 295-300. (PubMed)

77. Farries, T. C., Steuer, K. L. and Atkinson, J. P. (1990). "Evolutionary implications of a new bypass activation pathway of the complement system." Immunology Today 11(3): 78-80. (PubMed)

78. Fearon, D. T. and Locksley, R. M. (1996). "The instructive role of innate immunity in the acquired immune response." Science 272(5258): 50-53. (JSTOR | PubMed)

79. Finstad, C. L., Litman, G. W., Finstad, J. and Good, R. A. (1972). "The evolution of the immune response. 13. The characterization of purified erythrocyte agglutinins from two invertebrate species." Journal of Immunology 108(6): 1704-1711. (PubMed)

80. Finstad, J., Papermaster, B. W. and Good, R. A. (1964). "Evolution of the Immune Response. 2. Morphologic Studies on the Origin of the Thymus and Organized Lymphoid Tissue." Laboratory Investigation; a journal of technical methods and pathology 13: 490-512. (PubMed)

81. Flajnik M. (editor) (1998). "The immune systems of ectothermic vertebrates." Immunological Reviews 166: 1-384. (PubMed)

82. Flajnik, M. F. (1996). "The immune system of ectothermic vertebrates." Veternary Immunology and Immunopathology 54(1-4): 145-150. (PubMed)

83. Flajnik, M. F. (2002). "Comparative analyses of immunoglobulin genes: surprises and portents." Nature Reviews Immunology 2(9): 688-698. (Google Scholar | DOI | Journal | PubMed)

84. Flajnik, M. F. (2004). "Immunology: another manifestation of GOD." Nature 430(6996): 157-158. (Google Scholar | DOI | Journal | PubMed)

85. Flajnik, M. F., Canel, C., Kramer, J. and Kasahara, M. (1991). "Evolution of the major histocompatibility complex: molecular cloning of major histocompatibility complex class I from the amphibian Xenopus." Proceedings of the National Academy of Sciences 88(2): 537-541. (PubMed)

86. Flajnik, M. F., Canel, C., Kramer, J. and Kasahara, M. (1991). "Which came first, MHC class I or class II?" Immunogenetics 33(5-6): 295-300. (PubMed)

87. Flajnik, M. F. and Du Pasquier, L. (1990). "The major histocompatibility complex of frogs." Immunological Reviews 113: 47-63. (PubMed)

88. Flajnik, M. F. and Du Pasquier, L. (2004). "Evolution of innate and adaptive immunity: can we draw a line?" Trends in Immunology 25(12): 640-644. (Google Scholar | DOI | Journal | PubMed)

89. Flajnik, M. F. and Kasahara, M. (2001). "Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system." Immunity 15(3): 351-362. (PubMed)

90. Flajnik, M. F., Miller, K. and Du Pasquier, L. (2003). "Evolution of the Immune System." Fundamental Immunology. Edited by W. E. Paul. Philadelphia, Lippincott Williams & Wilkins: 519-570. (Library | Amazon | Google Print)

91. Flajnik, M. F., Ohta, Y., Namikawa-Yamada, C. and Nonaka, M. (1999). "Insight into the primordial MHC from studies in ectothermic vertebrates." Immunological Reviews 167: 59-67. (PubMed)

92. Flajnik, M. F. and Rumfelt, L. L. (2000). "Early and natural antibodies in non-mammalian vertebrates." Current Topics in Microbiology and Immunology 252: 233-240. (PubMed)

93. Flajnik, M. F. and Rumfelt, L. L. (2000). "The immune system of cartilaginous fish." Current Topics in Microbiology and Immunology 248: 249-270. (PubMed)

94. Frommel, D., Litman, G. W., Chartrand, S. L., Seal, U. S. and Good, R. A. (1971). "Carbohydrate composition in the evolution of the immunoglobulins." Immunochemistry 8(6): 573-577. (PubMed)

95. Frommel, D., Litman, G. W., Finstad, J. and Good, R. A. (1971). "The evolution of the immune response. 11. The immunoglobulins of the horned shark, Heterodontus francisci: purification, characterization and structural requirement for antibody activity." Journal of Immunology 106(5): 1234-1243. (PubMed)

96. Fugmann, S. D., Messier, C., Novack, L. A., Cameron, R. A. and Rast, J. P. (2006). "An ancient evolutionary origin of the Rag1/2 gene locus." Proceedings of the National Academy of Sciences 103(10): 3728-3733. (DOI | Journal | PubMed)

97. Fujita, T. (2002). "Evolution of the lectin-complement pathway and its role in innate immunity." Nature Reviews Immunology 2(5): 346-353. (PubMed)

98. Fujita, T., Endo, Y. and Nonaka, M. (2004). "Primitive complement system--recognition and activation." Molecular Immunology 41(2-3): 103-111. (PubMed)

99. Fujita, T., Matsushita, M. and Endo, Y. (2004). "The lectin-complement pathway--its role in innate immunity and evolution." Immunological Reviews 198: 185-202. (PubMed)

100. Galaktionov, V. G. (2004). "Evolutionary Development of the Immunoglobulin Family." Biology Bulletin 31(2): 101-111. (Google Scholar | DOI | Journal | PubMed)

101. Gellert, M. (1996). "A new view of V(D)J recombination." Genes to Cells 1(3): 269-275. (PubMed)

102. Gellert, M. (1997). "Recent advances in understanding V(D)J recombination." Advances in Immunology 64: 39-64. (PubMed)

103. Gellert, M. (2002). "V(D)J recombination: RAG proteins, repair factors, and regulation." Annual Review of Biochemistry 71: 101-132. (PubMed)

104. Gilbertson, P., Wotherspoon, J. and Raison, R. L. (1986). "Evolutionary development of lymphocyte heterogeneity: leucocyte subpopulations in the Pacific hagfish." Developmental and Comparative Immunology 10(1): 1-10. (PubMed)

105. Girardin, S. E. and Philpott, D. J. (2004). "Mini-review: the role of peptidoglycan recognition in innate immunity." European Journal of Immunology 34(7): 1777-1782. (PubMed)

106. Good, R. A. and Papermaster, B. W. (1964). "Ontogeny and Phylogeny of Adaptive Immunity." Advances in Immunology 27: 1-115. (PubMed)

107. Gould, S. J., Hildreth, J. E. and Booth, A. M. (2004). "The evolution of alloimmunity and the genesis of adaptive immunity." Quarterly Review of Biology 79(4): 359-382. (Google Scholar | DOI | Journal | PubMed)

108. Greenberg, A. S., Avila, D., Hughes, M., Hughes, A., McKinney, E. C. and Flajnik, M. F. (2002). "A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks." Nature 374(6518): 168-173. (Google Scholar | DOI | Journal | PubMed)

109. Grosberg, R. K. and Hart, M. W. (2000). "Mate selection and the evolution of highly polymorphic self/nonself recognition genes." Science 289(5487): 2111-2114. (PubMed)

110. Gross, P. S., Al-Sharif, W. Z., Clow, L. A. and Smith, L. C. (1999). "Echinoderm immunity and the evolution of the complement system." Developmental and Comparative Immunology 23(4-5): 429-442. (PubMed)

111. Gross, P. S., Clow, L. A. and Smith, L. C. (2000). "SpC3, the complement homologue from the purple sea urchin, Strongylocentrotus purpuratus, is expressed in two subpopulations of the phagocytic coelomocytes." Immunogenetics 51(12): 1034-1044. (PubMed)

112. Grossberger, D., Marcuz, A., Du Pasquier, L. and Lambris, J. D. (1989). "Conservation of structural and functional domains in complement component C3 of Xenopus and mammals." Proceedings of the National Academy of Sciences 86(4): 1323-1327. (PubMed)

113. Hagmann, M. (1997). "RAGged repair: what's new in V(D)J recombination." Biological Chemistry 378(8): 815-819. (PubMed)

114. Hanley, P. J., Hook, J. W., Raftos, D. A., Gooley, A. A., Trent, R. and Raison, R. L. (1992). "Hagfish humoral defense protein exhibits structural and functional homology with mammalian complement components." Proceedings of the National Academy of Sciences 89(17): 7910-7914. (PubMed)

115. Hansen, J. D. and McBlane, J. F. (2000). "Recombination-Activating Genes, Transposition, and the Lymphoid-Specific Combinatorial Immune System: A Common Evolutionary Connection." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 111-135. (Library | PubMed | Amazon | Google Print)

116. Harding, F. A., Cohen, N. and Litman, G. W. (1990). "Immunoglobulin heavy chain gene organization and complexity in the skate, Raja erinacea." Nucleic Acids Research 18(4): 1015-1020. (PubMed)

117. Harvell, C. D. (1990). "The evolution of inducible defence." Parasitology 100 Suppl: S53-61. (PubMed)

118. Hassanin, A., Golub, R., Lewis, S. M. and Wu, G. E. (2000). "Evolution of the recombination signal sequences in the Ig heavy-chain variable region locus of mammals." Proceedings of the National Academy of Sciences 97(21): 11415-11420. (PubMed)

119. Haynes, M. R. and Wu, G. E. (2004). "Evolution of the variable gene segments and recombination signal sequences of the human T-cell receptor alpha/delta locus." Immunogenetics 56(7): 470-479. (PubMed)

120. Hendrickson, E. A., Qin, X. Q., Bump, E. A., Schatz, D. G., Oettinger, M. and Weaver, D. T. (1991). "A link between double-strand break-related repair and V(D)J recombination: the scid mutation." Proceedings of the National Academy of Sciences 88(10): 4061-4065. (PubMed)

121. Hildemann, W. H. (1974). "Phylogeny of immune responsiveness in invertebrates." Life Sciences 14(4): 605-614. (PubMed)

122. Hildemann, W. H. and Reddy, A. L. (1973). "Phylogeny of immune responsiveness: marine invertebrates." Federation Proceedings 32(12): 2188-2194. (PubMed)

123. Hinds, K. R. and Litman, G. W. (1986). "Major reorganization of immunoglobulin VH segmental elements during vertebrate evolution." Nature 320(6062): 546-549. (PubMed)

124. Hinds-Frey, K. R., Nishikata, H., Litman, R. T. and Litman, G. W. (1993). "Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity." Journal of Experimental Medicine 178(3): 815-824. (PubMed)

125. Hiom, K., Melek, M. and Gellert, M. (1998). "DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations." Cell 94(4): 463-470. (Google Scholar | DOI | Journal | PubMed)

126. Hoffman, J. A., Janeway, C. A. and Natori, S., eds. (1994). Phylogenetic Perspectives in Immunity: The Insect Host Defense. Austin, R. G. Landes Company. (Library | Amazon | Google Print)

127. Hoffmann, J. A. (1995). "Innate immunity of insects." Current Opinion in Immunology 7(1): 4-10. (PubMed)

128. Hoffmann, J. A., Kafatos, F. C., Janeway, C. A. and Ezekowitz, R. A. (1999). "Phylogenetic perspectives in innate immunity." Science 284(5418): 1313-1318. (PubMed)

129. Hoffmann, J. A. and Reichhart, J. M. (2002). "Drosophila innate immunity: an evolutionary perspective." Nature Immunology 3(2): 121-126. (PubMed)

130. Holmes, E. C. (2004). "Adaptation and Immunity." PLoS Biology 2(9): 1269-1269. (Google Scholar | DOI | Journal | PubMed)

131. Hughes, A. L. and Yeager, M. (1997). "Molecular evolution of the vertebrate immune system." BioEssays 19(9): 777-786. (Google Scholar | PubMed)

132. Ishikawa, G., Azumi, K. and Yokosawa, H. (2000). "Involvement of tyrosine kinase and phosphatidylinositol 3-kinase in phagocytosis by ascidian hemocytes." Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 125(3): 351-357. (Journal | PubMed)

133. Iwanaga, S. and Kawabata, S. (1998). "Evolution and phylogeny of defense molecules associated with innate immunity in horseshoe crab." Frontiers in Bioscience 3: D973-984. (PubMed)

134. Iwanaga, S., Kawabata, S.-i., Miura, Y., Seki, N., Shigenaga, T. and Muta, T. (1994). "Clotting Cascade in the Immune Response of Horseshoe Crab." Phylogenetic Perspectives in Immunity: The Insect Host Defense. Edited by J. A. Hoffman, C. A. Janeway and S. Natori. Austin, R.G. Landes Company: 79-96. (Library | Amazon | Google Print)

135. Janssen, B. J. C., Huizinga1, E. G., Raaijmakers, H. C. A., Roos, A., Daha, M. R., Nilsson-Ekdahl, K., Nilsson, B. and Gros, P. (2005). "Structures of complement component C3 provide insights into the function and evolution of immunity." Nature 437(7058): 505-511. (Google Scholar | DOI | Journal | PubMed)

136. Ji, X., Azumi, K., Sasaki, M. and Nonaka, M. (1997). "Ancient origin of the complement lectin pathway revealed by molecular cloning of mannan binding protein-associated serine protease from a urochordate, the Japanese ascidian, Halocynthia roretzi." Proceedings of the National Academy of Sciences 94(12): 6340-6345. (Google Scholar | Journal | PubMed)

137. Joly, E. (2006). "Various hypotheses on MHC evolution suggested by the concerted evolution of CD94L and MHC class Ia molecules." Biology Direct 1(1): 3. (Google Scholar | DOI | Journal | PubMed)

138. Joly, E. and Rouillon, V. (2006). "The orthology of HLA-E and H2-Qa1 is hidden by their concerted evolution with other MHC class I molecules." Biology Direct 1(1): 2. (Google Scholar | DOI | Journal | PubMed)

139. Jones, J. M. (2004). "The taming of a transposon: V(D)J recombination and the immune system." Immunological Reviews 200(1): 233-248. (Google Scholar | DOI | Journal | PubMed)

140. Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R. and Kawabata, S. (2001). "The 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems." Proceedings of the National Academy of Sciences 98(24): 13519-13524. (PubMed)

141. Kapitonov, V. V. and Jurka, J. (2005). "RAG1 Core and V(D)J Recombination Signal Sequences Were Derived from Transib Transposons." PLoS Biology 3(6): e181:0001-0014. (Google Scholar | DOI | Journal | PubMed)

142. Kasahara, M., Flajnik, M. F., Ishibashi, T. and Natori, T. (1995). "Evolution of the major histocompatibility complex: a current overview." Transplant Immunology 3(1): 1-20. (PubMed)

143. Kasahara, M., McKinney, E. C., Flajnik, M. F. and Ishibashi, T. (1993). "The evolutionary origin of the major histocompatibility complex: polymorphism of class II alpha chain genes in the cartilaginous fish." European Journal of Immunology 23(9): 2160-2165. (PubMed)

144. Kasahara, M., Suzuki, T. and Du Pasquier, L. (2004). "On the origins of the adaptive immune system: novel insights from invertebrates and cold-blooded vertebrates." Trends in Immunology 25(2): 105-111. (PubMed)

145. Kasahara, M., Vazquez, M., Sato, K., McKinney, E. C. and Flajnik, M. F. (1992). "Evolution of the major histocompatibility complex: isolation of class II A cDNA clones from the cartilaginous fish." Proceedings of the National Academy of Sciences 89(15): 6688-6692. (PubMed)

146. Kaufman, J. (2002). "The origins of the adaptive immune system: whatever next?" Nature Immunology 3(12): 1124-1125. (Google Scholar | DOI | Journal | PubMed)

147. Kelsoe, G. and Schulze, D. H., eds. (1987). Evolution and Vertebrate Immunity: The Antigen-Receptor and MHC Gene Families. Austin, University of Texas Press. (Library | Amazon | Google Print)

148. Kennedy, A. K., Guhathakurta, A., Kleckner, N. and Haniford, D. B. (1998). "Tn10 transposition via a DNA hairpin intermediate." Cell 95(1): 125-134. (PubMed)

149. Khalturin, K., Panzer, Z., Cooper, M. D. and Bosch, T. C. (2004). "Recognition strategies in the innate immune system of ancestral chordates." Molecular Immunology 41(11): 1077-1087. (PubMed)

150. Kimbrell, D. A. and Beutler, B. (2001). "The evolution and genetics of innate immunity." Nature Reviews Genetics 2(4): 256-267. (PubMed)

151. Klapper, D. G. and Clem, L. W. (1977). "Phylogeny of immunoglobulin structure and function; characterization of the cysteine-containing peptide involved in the pentamerization of shark IgM." Developmental and Comparative Immunology 1(2): 81-91. (PubMed)

152. Klein, J. (1986). "Evolution of Mhc." Natural History of the Major Histocompatibility Complex. New York, John Wiley & Sons: 715-762. (Library | Google Print)

153. Klein, J. (1997). "Homology Between Immune Responses in Vertebrates and Invertebrates: Does it Exist?" Scandinavian Journal of Immunology 46(6): 558-564. (Google Scholar | Journal | PubMed)

154.* Klein, J. and Nikolaidis, N. (2005). "The descent of the antibody-based immune system by gradual evolution." Proceedings of the National Academy of Sciences 102(1): 169-174. (Google Scholar | DOI | Journal | PubMed)

155. Kokubu, F., Litman, R., Shamblott, M. J., Hinds, K. and Litman, G. W. (1988). "Diverse organization of immunoglobulin VH gene loci in a primitive vertebrate." The EMBO Journal 7(11): 3413-3422. (PubMed)

156. Krem, M. M. and Di Cera, E. (2002). "Evolution of enzyme cascades from embryonic development to blood coagulation." Trends in Biochemical Sciences 27(2): 67-74. (Google Scholar | DOI | Journal | PubMed)

157. Lachmann, P. J. (1998). "Microbial immunology: a new mechanism for immune subversion." Current Biology 8(3): R99-R101. (PubMed)

158. Lachmann, P. J. and Hobart, M. J. (1979). "The genetics of the complement system." Ciba Foundation Symposium(66): 231-250. (PubMed)

159. Laird, D. J. (2002). "Immune System." Encyclopedia of Evolution. Edited by M. Pagel. Oxford, Oxford University Press. 2: 558-564. (Library | Publisher | Amazon | Google Print)

160. Laird, D. J., De Tomaso, A. W., Cooper, M. D. and Weissman, I. L. (2000). "50 million years of chordate evolution: seeking the origins of adaptive immunity." Proceedings of the National Academy of Sciences 97(13): 6924-6926. (PubMed)

161. Langman, R. E. (1989). The immune system: Evolutionary principles guide our understanding of this complex biological defense system. San Diego, Academic Press, Inc.

162. Langman, R. E. and Cohn, M. (1992). "What is the selective pressure that maintains the gene loci encoding the antigen receptors of T and B cells? A hypothesis." Immunology and Cell Biology 70 ( Pt 6): 397-404. (PubMed)

163. Langman, R. E. and Cohn, M. (2002). "If the immune repertoire evolved to be large, random, and somatically generated, then." Cellular Immunology 216(1-2): 15-22. (PubMed)

164. Lawlor, D. A., Zemmour, J., Ennis, P. D. and Parham, P. (1990). "Evolution of Class-I MHC Genes and Proteins: From Natural Selection to Thymic Selection." Annual Review of Immunology 8: 23-63. (DOI | Journal | PubMed)

165. Lee, S. S., Fitch, D., Flajnik, M. F. and Hsu, E. (2000). "Rearrangement of immunoglobulin genes in shark germ cells." Journal of Experimental Medicine 191(10): 1637-1648. (PubMed)

166. Leslie, G. A. and Clem, L. W. (1972). "Phylogeny of immunoglobulin structure and function. VI. 17S, 7.5S and 5.7S anti-DNP of the turtle, Pseudamys scripta." Journal of Immunology 108(6): 1656-1664. (PubMed)

167. Lewis, S. M. (1994). "The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses." Advances in Immunology 56: 27-150. (PubMed)

168. Lewis, S. M. (1999). "Evolution of Immunoglobulin and T-Cell Receptor Gene Assembly." Annals of the New York Academy of Sciences 870: 58-67. (Google Scholar | Journal | PubMed)

169. Lewis, S. M. and Wu, G. E. (1997). "The origins of V(D)J recombination." Cell 88(2): 159-162. (Google Scholar | DOI | Journal | PubMed)

170. Lewis, S. M. and Wu, G. E. (2000). "The old and the restless." Journal of Experimental Medicine 191(10): 1631-1636. (Google Scholar | DOI | Journal | PubMed)

171. Liddington, R. and Bankston, L. (2005). "Structural biology: origins of chemical biodefence." Nature 437(7058): 484-485. (PubMed)

172. Lindstrom-Dinnetz, I., Sun, S. C. and Faye, I. (1995). "Structure and expression of Hemolin, an insect member of the immunoglobulin gene superfamily." European Journal of Biochemistry 230(3): 920-925. (PubMed)

173. Litman, G. W. (1975). "Relationship between structure and function of lower vertebrate immunoglobulins." Advances in Experimental Medicine and Biology 64: 217-228. (PubMed)

174. Litman, G. W. (1996). "Sharks and the origins of vertebrate immunity." Scientific American 275(5): 67-71. (Journal | PubMed)

175. Litman, G. W. (2005). "Histocompatibility: colonial match and mismatch." Nature 438(7067): 437-439. (DOI | Journal | PubMed)

176. Litman, G. W., Amemiya, C. T., Harding, F. A., Haire, R. N., Hinds, K. R., Litman, R. T., Ohta, Y., Shamblott, M. J. and Varner, J. A. (1991). "Evolutionary development of immunoglobulin gene diversity." Advances in Experimental Medicine and Biology 292: 11-17. (PubMed)

177. Litman, G. W., Anderson, M. K. and Rast, J. P. (1999). "Evolution of antigen binding receptors." Annual Review of Immunology 17: 109-147. (Google Scholar | DOI | Journal | PubMed)

178. Litman, G. W., Berger, L., Murphy, K., Litman, R., Hinds, K. and Erickson, B. W. (1985). "Immunoglobulin VH gene structure and diversity in Heterodontus, a phylogenetically primitive shark." Proceedings of the National Academy of Sciences 82(7): 2082-2086. (PubMed)

179. Litman, G. W., Berger, L., Murphy, K., Litman, R., Podlaski, F., Hinds, K., Jahn, C. L., Dingerkus, G. and Erickson, B. W. (1984). "Phylogenetic diversification of immunoglobulin VH genes." Developmental and Comparative Immunology 8(3): 499-514. (PubMed)

180. Litman, G. W., Cannon, J. P. and Dishaw, L. J. (2005). "Reconstructing immune phylogeny: new perspectives." Nature Reviews Immunology 5(11): 866-879. (PubMed)

181. Litman, G. W., Cannon, J. P. and Rast, J. P. (2005). "New insights into alternative mechanisms of immune receptor diversification." Advances in Immunology 87: 209-236. (PubMed)

182. Litman, G. W., Erickson, B. W., Lederman, L. and Makela, O. (1982). "Antibody response in Heterodontus." Molecular and Cellular Biochemistry 45(1): 49-57. (PubMed)

183. Litman, G. W., Finstad, F. J., Howell, J., Pollara, B. W. and God, R. A. (1970). "The evolution of the immune response. 3. Structural studies of the lamprey immuoglobulin." Journal of Immunology 105(5): 1278-1285. (PubMed)

184. Litman, G. W., Fromme, D., Chartrand, S. L., Finstad, J. and Good, R. A. (1971). "Significance of heavy chain mass and antigenic relationship in immunoglobulin evolution." Immunochemistry 8(4): 345-349. (PubMed)

185. Litman, G. W., Frommel, D., Finstad, J. and Good, R. A. (1971). "Evolution of the immune response. 10. Immunoglobulins of the bowfin: subunit nature." Journal of Immunology 107(3): 881-888. (PubMed)

186. Litman, G. W., Frommel, D., Finstad, J. and Good, R. A. (1971). "The evolution of the immune reponse. 9. Immunoglobulins of the bowfin: purification and characterization." Journal of Immunology 106(3): 747-754. (PubMed)

187. Litman, G. W., Frommel, D., Rosenberg, A. and Good, R. A. (1971). "Circular dichroic analysis of immunoglobulins in phylogenetic perspective." Biochimica et Biophysica Acta 236(3): 647-654. (PubMed)

188. Litman, G. W., Haire, R. N., Hinds, K. R., Amemiya, C. T., Rast, J. P. and Hulst, M. (1992). "Evolutionary development of the B-cell repertoire." Annals of the New York Academy of Sciences 651: 360-368. (PubMed)

189. Litman, G. W., Hinds, K., Berger, L., Murphy, K. and Litman, R. (1985). "Structure and organization of immunoglobulin VH genes in Heterodontus, a phylogenetically primitive shark." Developmental and Comparative Immunology 9(4): 749-758. (PubMed)

190. Litman, G. W., Hinds, K. R., Litman, R. T. and Kokubu, F. (1987). "The early phylogenetic origin of antibody gene structure and function." Progress in Clinical and Biological Research 233: 1-11. (PubMed)

191. Litman, G. W., Rast, J. P., Shamblott, M. J., Haire, R. N., Hulst, M., Roess, W., Litman, R. T., Hinds-Frey, K. R., Zilch, A. and Amemiya, C. T. (1993). "Phylogenetic diversification of immunoglobulin genes and the antibody repertoire." Molecular Biology and Evolution 10(1): 60-72. (PubMed)

192. Litman, G. W., Rosenberg, A., Frommel, D., Pollara, B., Finstad, J. and Good, R. A. (1971). "Biophysical studies of the immunoglobulins. The circular dichroic spectra of the immunoglobulins--a phylogenetic comparison." International Archives of Allergy and Immunology 40(4-5): 551-575. (PubMed)

193. Litman, G. W., Scheffel, C. and Gerber-Jenson, B. (1980). "Immunoglobulin diversity in the phylogenetically primitive shark, Heterodontus francisci. Suggested lack of structural variation between light chains isolated from different animals." Journal of Immunogenetics 7(3): 197-206. (PubMed)

194. Litman, G. W., Stolen, J. S., Sarvas, H. O. and Makela, O. (1982). "The range and fine specificity of the anti-hapten immune response: phylogenetic studies." Journal of Immunogenetics 9(6): 465-474. (PubMed)

195. Lobb, C. J. and Clem, L. W. (1981). "Phylogeny of immunoglobulin structure and function-XII. Secretory immunoglobulins in the bile of the marine teleost Archosargus probatocephalus." Molecular Immunology 18(7): 615-619. (PubMed)

196. Lobb, C. J. and Clem, L. W. (1981). "Phylogeny of immunoglobulin structure and function. XI. Secretory immunoglobulins in the cutaneous mucus of the sheepshead, Archosargus probatocephalus." Developmental and Comparative Immunology 5(4): 587-596. (PubMed)

197. Lobb, C. J. and Clem, W. (1981). "Phylogeny of immunoglobulin in structure and function-x. Humoral immunoglobulins of the sheepshead, Archosargus probatocephalus." Developmental and Comparative Immunology 5(2): 271-282. (PubMed)

198. Magor, B. G., De Tomaso, A., Rinkevich, B. and Weissman, I. L. (1999). "Allorecognition in colonial tunicates: protection against predatory cell lineages?" Immunological Reviews 167: 69-79. (PubMed)

199. Magor, B. G. and Magor, K. E. (2001). "Evolution of effectors and receptors of innate immunity." Developmental and Comparative Immunology 25(8-9): 651-682. (PubMed)

200. Makela, O., Koskimies, S. and Karjalainen, K. (1976). "Possible evolution of acquired immunity from self-recognition structures." Scandinavian Journal of Immunology 5(4): 305-310. (PubMed)

201. Manning, M. J., ed. (1980). Phylogeny of Immunological Memory. Developments in Immunology. Amsterdam, Elsevier/North-Holland Biomedical Press. (Library | Amazon | Google Print)

202. Marchalonis, J. and Edelman, G. M. (1965). "Phylogenetic origins of antibody structure. I. Multichain structure of immunoglobulins in the smooth dogfish (Mustelus canis)." Journal of Experimental Medicine 122(3): 601-618. (PubMed)

203. Marchalonis, J. and Edelman, G. M. (1966). "Phylogenetic origins of antibody structure. II. Immunoglobulins in the primary immune response of the bullfrog, Rana catesbiana." Journal of Experimental Medicine 124(5): 901-913. (PubMed)

204. Marchalonis, J. J. (1976). Immunity in Evolution. Cambridge, Mass., Harvard University Press. (Library | Amazon | Google Print)

205. Marchalonis, J. J., Adelman, M. K., Schluter, S. F. and Ramsland, P. A. (2006). "The antibody repertoire in evolution: Chance, selection, and continuity." Developmental and Comparative Immunology 30(1-2): 223-247. (Google Scholar | DOI | Journal | PubMed)

206. Marchalonis, J. J., Adelman, M. K., Zeitler, B. J., Sarazin, P. M., Jaqua, P. M. and Schluter, S. F. (2001). "Evolutionary factors in the emergence of the combinatorial germline antibody repertoire." Advances in Experimental Medicine and Biology 484: 13-30. (PubMed)

207. Marchalonis, J. J., Bernstein, R. M., Shen, S. X. and Schluter, S. F. (1996). "Emergence of the immunoglobulin family: conservation in protein sequence and plasticity in gene organization." Glycobiology 6(7): 657-663. (PubMed)

208. Marchalonis, J. J. and Cone, R. E. (1973). "The phylogenetic emergence of vertebrate immunity." Australian Journal of Experimental Biology and Medical Science 51(4): 461-488. (PubMed)

209. Marchalonis, J. J., Decker, J. M., DeLuca, D., Moseley, J. M., Smith, P. and Warr, G. W. (1977). "Lymphocyte surface immunoglobulins: evolutionary origins and involvement in activation." Cold Spring Harbor Symposium on Quantitative Biology 41 Pt 1: 261-273. (Journal | PubMed)

210. Marchalonis, J. J. and Edelman, G. M. (1968). "Phylogenetic origins of antibody structure. 3. Antibodies in the primary immune response of the sea lamprey, Petromyzon marinus." Journal of Experimental Medicine 127(5): 891-914. (PubMed)

211. Marchalonis, J. J., Hohman, V. S., Kaymaz, H., Schluter, S. F. and Edmundson, A. B. (1994). "Cell Surface Recognition and the Immunoglobulin Superfamily." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 20-33. (Library | PubMed | Publisher | Google Print)

212. Marchalonis, J. J., Jensen, I. and Schluter, S. F. (2002). "Structural, antigenic and evolutionary analyses of immunoglobulins and T cell receptors." Journal of Molecular Recognition 15(5): 260-271. (Google Scholar | DOI | Journal | PubMed)

213. Marchalonis, J. J., Kaveri, S., Lacroix-Desmazes, S. and Kazatchkine, M. D. (2002). "Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system." FASEB Journal 16(8): 842-848. (Google Scholar | Journal | PubMed)

214. Marchalonis, J. J. and Schluter, S. F. (1989). "Evolution of variable and constant domains and joining segments of rearranging immunoglobulins." FASEB Journal 3(13): 2469-2479. (PubMed)

215. Marchalonis, J. J. and Schluter, S. F. (1989). "Immunoproteins in evolution." Developmental and Comparative Immunology 13(4): 285-301. (PubMed)

216. Marchalonis, J. J. and Schluter, S. F. (1990). "On the relevance of invertebrate recognition and defence mechanisms to the emergence of the immune response of vertebrates." Scandinavian Journal of Immunology 32(1): 13-20. (PubMed)

217. Marchalonis, J. J. and Schluter, S. F. (1994). "Development of an Immune System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 1-11. (Library | PubMed | Publisher | Google Print)

218. Marchalonis, J. J. and Schluter, S. F. (1998). "A stochastic model for the rapid emergence of specific vertebrate immunity incorporating horizontal transfer of systems enabling duplication and combinational diversification." Journal of Theoretical Biology 193(3): 429-444. (PubMed)

219. Marchalonis, J. J., Schluter, S. F., Bernstein, R. M. and Hohman, V. S. (1998). "Antibodies of sharks: revolution and evolution." Immunological Reviews 166: 103-122. (PubMed)

220. Marchalonis, J. J., Schluter, S. F., Bernstein, R. M., Shen, S. and Edmundson, A. B. (1998). "Phylogenetic emergence and molecular evolution of the immunoglobulin family." Advances in Immunology 70: 417-506. (PubMed)

221. Marchalonis, J. J. and Warr, G. W. (1978). "Phylogenetic origins of immune recognition: naturally occurring DNP-binding molecules in chordate sera and hemolymph." Developmental and Comparative Immunology 2(3): 443-459. (PubMed)

222. Marchalonis, J. J., Warr, G. W. and Ruben, L. N. (1978). "Evolutionary immunobiology and the problem of the T-cell receptor." Developmental and Comparative Immunology 2(2): 203-218. (PubMed)

223. Market, E. and Papavasiliou, F. N. (2003). "V(D)J Recombination and the Evolution of the Adaptive Immune System." PLoS Biology 1(1): 24-27. (Google Scholar | DOI | Journal | PubMed)

224. Martinelli, C. and Reichhart, J. M. (2005). "Evolution and integration of innate immune systems from fruit flies to man: lessons and questions." Journal of Endotoxin Research 11(4): 243-248. (PubMed)

225. Matsunaga, T. and Rahman, A. (1998). "What brought the adaptive immune system to vertebrates?--The jaw hypothesis and the seahorse." Immunological Reviews 166: 177-186. (PubMed)

226. Matsushita, M., Endo, Y., Nonaka, M. and Fujita, T. (1998). "Complement-related serine proteases in tunicates and vertebrates." Current Opinion in Immunology 10(1): 29-35. (PubMed)

227. Mayer, W. E., Uinuk-Ool, T., Tichy, H., Gartland, L. A., Klein, J. and Cooper, M. D. (2002). "Isolation and characterization of lymphocyte-like cells from a lamprey." Proceedings of the National Academy of Sciences 99(22): 14350-14355. (Google Scholar | DOI | Journal | PubMed)

228. McBlane, J. F., van Gent, D. C., Ramsden, D. A., Romeo, C., Cuomo, C. A., Gellert, M. and Oettinger, M. A. (1995). "Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps." Cell 83(3): 387-395. (PubMed)

229. Medzhitov, R. and Janeway, C. A., Jr. (1997). "Innate immunity: the virtues of a nonclonal system of recognition." Cell 91(3): 295-298. (PubMed)

230. Medzhitov, R. and Janeway, C. A., Jr. (1998). "An ancient system of host defense." Current Opinion in Immunology 10(1): 12-15. (PubMed)

231. Medzhitov, R., Preston-Hurlburt, P. and Janeway, C. A., Jr. (1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity." Nature 388(6640): 394-397. (PubMed)

232. Meister, M., Hetru, C. and Hoffmann, J. A. (2000). "The antimicrobial host defense of Drosophila." Current Topics in Microbiology and Immunology 248: 17-36. (PubMed)

233. Menezes, H. and Jared, C. (2002). "Immunity in plants and animals: common ends through different means using similar tools." Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 132(1): 1-7. (Journal | PubMed)

234. Merz, D. C., Finstad, C. L., Litman, G. W. and Good, R. A. (1975). "Aspects of vertebrate immunoglobulin evolution. Constancy in light chain electrophoretic behavior." Immunochemistry 12(6-7): 499-504. (PubMed)

235. Messier, T. L., O'Neill, J. P., Hou, S.-M., Nicklas, J. A. and Finette, B. A. (2003). "In vivo transposition mediated by V(D)J recombinase in human T lymphocytes." The EMBO Journal 22(6): 1381-1388. (Google Scholar | DOI | Journal | PubMed)

236. Metchnikoff, E. (1891 [1968]). Lectures on the comparative pathology of inflammation; delivered at the Pasteur Institute in 1891. Dover, New York.

237. Miyazawa, S., Azumi, K. and Nonaka, M. (2001). "Cloning and characterization of integrin alpha subunits from the solitary ascidian, Halocynthia roretzi." Journal of Immunology 166(3): 1710-1715. (PubMed)

238. Miyazawa, S. and Nonaka, M. (2004). "Characterization of novel ascidian beta integrins as primitive complement receptor subunits." Immunogenetics 55(12): 836-844. (PubMed)

239. Mushegian, A. and Medzhitov, R. (2001). "Evolutionary perspective on innate immune recognition." Journal of Cell Biology 155(5): 705-710. (PubMed)

240. Muta, T. and Iwanaga, S. (1996). "The role of hemolymph coagulation in innate immunity." Current Opinion in Immunology 8(1): 41-47. (PubMed)

241. Nair, S. V., Pearce, S., Green, P. L., Mahajan, D., Newton, R. A. and Raftos, D. A. (2000). "A collectin-like protein from tunicates." Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 125(2): 279-289. (Journal | PubMed)

242. Neuberger, M. S. (2002). "Novartis Medal Lecture. Antibodies: a paradigm for the evolution of molecular recognition." Biochemical Society Transactions 30(4): 341-350. (Journal | PubMed)

243. Newton, R. A., Raftos, D. A., Raison, R. L. and Geczy, C. L. (1994). "Chemotactic responses of hagfish (Vertebrata, Agnatha) leucocytes." Developmental and Comparative Immunology 18(4): 295-303. (PubMed)

244. Nonaka, M. (2000). "Origin and evolution of the Complement System." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 37-50. (Library | PubMed | Amazon | Google Print)

245. Nonaka, M. (2001). "Evolution of the complement system." Current Opinion in Immunology 13(1): 69-73. (PubMed)

246. Nonaka, M. and Azumi, K. (1999). "Opsonic complement system of the solitary ascidian, Halocynthia roretzi." Developmental and Comparative Immunology 23(4-5): 421-427. (PubMed)

247. Nonaka, M., Azumi, K., Ji, X., Namikawa-Yamada, C., Sasaki, M., Saiga, H., Dodds, A. W., Sekine, H., Homma, M. K., Matsushita, M., Endo, Y. and Fujita, T. (1999). "Opsonic complement component C3 in the solitary ascidian, Halocynthia roretzi." Journal of Immunology 162(1): 387-391. (PubMed)

248. Nonaka, M., Fujii, T., Kaidoh, T., Natsuume-Sakai, S., Yamaguchi, N. and Takahashi, M. (1984). "Purification of a lamprey complement protein homologous to the third component of the mammalian complement system." Journal of Immunology 133(6): 3242-3249. (PubMed)

249. Nonaka, M. and Miyazawa, S. (2001). "Evolution of the Initiating Enzymes of the Complement System." Genome Biology 3(1): 1001.1001-1001.1005. (Google Scholar | DOI | Journal | PubMed)

250. Nonaka, M. and Smith, S. L. (2000). "Complement system of bony and cartilaginous fish." Fish & Shellfish Immunology 10(3): 215-228. (PubMed)

251. Nonaka, M. and Takahashi, M. (1992). "Complete complementary DNA sequence of the third component of complement of lamprey. Implication for the evolution of thioester containing proteins." Journal of Immunology 148(10): 3290-3295. (PubMed)

252. Nonaka, M., Takahashi, M. and Sasaki, M. (1994). "Molecular cloning of a lamprey homologue of the mammalian MHC class III gene, complement factor B." Journal of Immunology 152(5): 2263-2269. (PubMed)

253. Nonaka, M. and Yoshizaki, F. (2004). "Primitive complement system of invertebrates." Immunological Reviews 198: 203-215. (PubMed)

254. Nonaka, M. and Yoshizaki, F. (2004). "Evolution of the Complement System." Molecular Immunology 40(12): 897-902. (Google Scholar | DOI | Journal | PubMed)

255. Nurnberger, T. and Brunner, F. (2002). "Innate immunity in plants and animals: emerging parallels between the recognition of general elicitors and pathogen-associated molecular patterns." Current Opinion in Plant Biology 5(4): 318-324. (PubMed)

256. Oettinger, M. A., Schatz, D. G., Gorka, C. and Baltimore, D. (1990). "RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination." Science 248(4962): 1517-1523. (PubMed)

257. Ohinata, Y., Sutou, S. and Mitsui, Y. (2003). "A novel testis-specific RAG2-like protein, Peas: its expression in pachytene spermatocyte cytoplasm and meiotic chromatin." FEBS Letters 537(1-3): 1-5. (PubMed)

258. Ohno, S. (1994). "MHC Evolution and Development of a Recognition System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 13-19. (Library | PubMed | Publisher | Google Print)

259. Opal, S. M. (2000). "Phylogenetic and functional relationships between coagulation and the innate immune response." Critical Care Medicine 28(9): S77-S80. (Google Scholar | Journal | PubMed)

260. Opal, S. M. (2004). "The nexus between systemic inflammation and disordered coagulation in sepsis." Journal of Endotoxin Research 10(2): 125-129. (PubMed)

261. Ota, T., Rast, J. P., Litman, G. W. and Amemiya, C. T. (2003). "Lineage-restricted retention of a primitive immunoglobulin heavy chain isotype within the Dipnoi reveals an evolutionary paradox." Proceedings of the National Academy of Sciences 100(5): 2501-2506. (PubMed)

262. Pancer, Z., Amemiya, C. T., Ehrhardt, G. R. A., Ceitlin, J., Gartland, G. L. and Cooper, M. D. (2004). "Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey." Nature 430(6996): 174-180. (Google Scholar | DOI | Journal | PubMed)

263. Pancer, Z. and Cooper, M. D. (2006). "The Evolution of Adaptive Immunity." Annual Review of Immunology 24. (DOI | Journal | PubMed)

264. Pancer, Z., Saha, N. R., Kasamatsu, J., Suzuki, T., Amemiya, C. T., Kasahara, M. and Cooper, M. D. (2005). "Variable lymphocyte receptors in hagfish." Proceedings of the National Academy of Sciences 102(26): 9224-9229. (PubMed)

265. Papermaster, B. W., Condie, R. M., Finstad, J. and Good, R. A. (1964). "Evolution of the Immune Response. 1. The Phylogenetic Development of Adaptive Immunologic Responsiveness in Vertebrates." Journal of Experimental Medicine 119: 105-130. (PubMed)

266. Parham P. (editor) (1999). "Genomic organisation of the MHC: structure, origin and function." Immunological Reviews 167: 1-379. (Google Scholar)

267. Perey, D. Y., Finstad, J., Pollara, B. and Good, R. A. (1968). "Evolution of the immune response. 6. First and second set skin homograft rejections in primitive fishes." Laboratory Investigation; a journal of technical methods and pathology 19(6): 591-597. (PubMed)

268. Plasterk, R. (1998). "Ragtime jumping." Nature 394(6695): 718-719. (Google Scholar | DOI | Journal | PubMed)

269. Plouffe, D. A., Hanington, P. C., Walsh, J. G., Wilson, E. C. and Belosevic, M. (2005). "Comparison of select innate immune mechanisms of fish and mammals." Xenotransplantation 12(4): 266-277. (PubMed)

270. Poitrineau, K., Brown, S. P. and Hochberg, M. E. (2004). "The joint evolution of defence and inducibility against natural enemies." Journal of Theoretical Biology 231(3): 389-396. (PubMed)

271. Pollara, B., Litman, G. W., Finstad, J., Howell, J. and Good, R. A. (1970). "The evolution of the immune response. 7. Antibody to human "O" cells and properties of the immunoglobulin in lamprey." Journal of Immunology 105(3): 738-745. (PubMed)

272. Prugnolle, F., Manica, A., Charpentier, M., Guegan, J. F., Guernier, V. and Balloux, F. (2005). "Pathogen-driven selection and worldwide HLA class I diversity." Current Biology 15(11): 1022-1027. (PubMed)

273. Quigley, J. P. and Armstrong, P. B. (1983). "An endopeptidase inhibitor found in Limulus plasma: an ancient form of alpha 2-macroglobulin." Annals of the New York Academy of Sciences 421: 119-124. (PubMed)

274. Quigley, J. P. and Armstrong, P. B. (1985). "A homologue of alpha 2-macroglobulin purified from the hemolymph of the horseshoe crab Limulus polyphemus." Journal of Biological Chemistry 260(23): 12715-12719. (PubMed)

275. Raftos, D. and Nair, S. (2004). "Tunicate cytokine-like molecules and their involvement in host defense responses." Progress in Molecular and Subcellular Biology 34: 165-182. (PubMed)

276. Raison, R. L. and Hildemann, W. H. (1984). "Immunoglobulin-bearing blood leucocytes in the Pacific hagfish." Developmental and Comparative Immunology 8(1): 99-108. (PubMed)

277. Ramsland, P. A., Kaushik, A., Marchalonis, J. J. and Edmundson, A. B. (2001). "Incorporation of long CDR3s into V domains: implications for the structural evolution of the antibody-combining site." Experimental and Clinical Immunogenetics 18(4): 176-198. (DOI | Journal | PubMed)

278. Rast, J. P., Anderson, M. K., Ota, T., Litman, R. T., Margittai, M., Shamblott, M. J. and Litman, G. W. (1994). "Immunoglobulin light chain class multiplicity and alternative organizational forms in early vertebrate phylogeny." Immunogenetics 40(2): 83-99. (PubMed)

279. Rast, J. P., Anderson, M. K., Strong, S. J., Luer, C., Litman, R. T. and Litman, G. W. (1997). "alpha, beta, gamma, and delta T cell antigen receptor genes arose early in vertebrate phylogeny." Immunity 6(1): 1-11. (PubMed)

280. Rast, J. P. and Litman, G. W. (1994). "T-cell receptor gene homologs are present in the most primitive jawed vertebrates." Proceedings of the National Academy of Sciences 91(20): 9248-9252. (PubMed)

281. Rast, J. P. and Litman, G. W. (1998). "Towards understanding the evolutionary origins and early diversification of rearranging antigen receptors." Immunological Reviews 166: 79-86. (PubMed)

282. Reinisch, C. L. and Litman, G. W. (1989). "Evolutionary immunobiology." Immunology Today 10(8): 278-281. (PubMed)

283. Richards, M. H. and Nelson, J. L. (2000). "The Evolution of Vertebrate Antigen Receptors: A Phylogenetic Approach." Molecular Biology and Evolution 17(1): 146-155. (Google Scholar | Journal | PubMed)

284. Rinkevich, B. (2004). "Primitive immune systems: are your ways my ways?" Immunological Reviews 198: 25-35. (PubMed)

285. Roth, D. B. (2000). "From lymphocytes to sharks: V(D)J recombinase moves to the germline." Genome Biology 1(2): 1014.1011-1014.1014. (Google Scholar | DOI | Journal | PubMed)

286. Roth, D. B., Nakajima, P. B., Menetski, J. P., Bosma, M. J. and Gellert, M. (1992). "V(D)J recombination in mouse thymocytes: double-strand breaks near T cell receptor delta rearrangement signals." Cell 69(1): 41-53. (PubMed)

287. Rothenberg, E. V. and Davidson, E. H. (2003). "Regulatory Co-options in the Evolution of Deuterostome Immune Systems." Innate Immunity. Edited by R. A. B. Ezekowitz and J. A. Hoffman. Totowa, NJ, Humana Press: 61-87. (Google Print)

288. Rothenberg, E. V. and Pant, R. (2004). "Origins of lymphocyte developmental programs: transcription factor evidence." Seminars in Immunology 16(4): 227-238. (Google Scholar | DOI | Journal | PubMed)

289. Ruben, L. N., Warr, G. W., Decker, J. M. and Marchalonis, J. J. (1977). "Phylogenetic origins of immune recognition: lymphoid heterogeneity and the hapten/carrier effect in the goldfish, Carassius auratus." Cellular Immunology 31(2): 266-283. (PubMed)

290. Rumfelt, L. L., Avila, D., Diaz, M., Bartl, S., McKinney, E. C. and Flajnik, M. F. (2001). "A shark antibody heavy chain encoded by a nonsomatically rearranged VDJ is preferentially expressed in early development and is convergent with mammalian IgG." Proceedings of the National Academy of Sciences 98(4): 1775-1780. (PubMed)

291. Sahu, A. and Lambris, J. D. (2001). "Structure and biology of complement protein C3, a connecting link between innate and acquired immunity." Immunological Reviews 180: 35-48. (PubMed)

292. Sahu, A., Sunyer, J. O., Moore, W. T., Sarrias, M. R., Soulika, A. M. and Lambris, J. D. (1998). "Structure, functions, and evolution of the third complement component and viral molecular mimicry." Immunologic Research 17(1-2): 109-121. (PubMed)

293. Saito, Y., Hirose, E. and Watanabe, H. (1994). "Allorecognition in compound ascidians." International Journal of Developmental Biology 38(2): 237-247. (PubMed)

294. Sakano, H., Hüppi, K., Heinrich, G. and Tonegawa, S. (1979). "Sequences at the somatic recombination sites of immunoglobulin light-chain genes." Nature 280(6): 288-294. (Google Scholar | DOI | Journal | PubMed)

295. Sato, K., Flajnik, M. F., Du Pasquier, L., Katagiri, M. and Kasahara, M. (1993). "Evolution of the MHC: isolation of class II beta-chain cDNA clones from the amphibian Xenopus laevis." Journal of Immunology 150(7): 2831-2843. (PubMed)

296. Schatz, D. G. (1999). "Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system." Immunologic Research 19(2-3): 169-182. (Google Scholar | PubMed)

297. Schatz, D. G. (2004). "Antigen receptor genes and the evolution of a recombinase." Seminars in Immunology 16(4): 245-256. (Google Scholar | DOI | Journal | PubMed)

298. Schatz, D. G., Oettinger, M. A. and Baltimore, D. (1989). "The V(D)J recombination activating gene, RAG-1." Cell 59(6): 1035-1048. (PubMed)

299. Schatz, D. G., Oettinger, M. A. and Schlissel, M. S. (1992). "V(D)J recombination: molecular biology and regulation." Annual Review of Immunology 10: 359-383. (PubMed)

300. Schatz, D. G. and Spanopoulou, E. (2005). "Biochemistry of V(D)J recombination." Current Topics in Microbiology and Immunology 290: 49-85. (Google Scholar | Journal | PubMed)

301. Schluter, S. F., Bernstein, R. M., Bernstein, H. and Marchalonis, J. J. (1999). "'Big Bang' emergence of the combinatorial immune system." Developmental and Comparative Immunology 23(2): 107-111. (Google Scholar | DOI | Journal | PubMed)

302. Schluter, S. F., Bernstein, R. M. and Marchalonis, J. J. (1997). "Molecular origins and evolution of immunoglobulin heavy-chain genes of jawed vertebrates." Immunology Today 18(11): 543-549. (Google Scholar | DOI | Journal | PubMed)

303. Schluter, S. F., Hohman, V. S., Edmundson, A. B. and Marchalonis, J. J. (1989). "Evolution of immunoglobulin light chains: cDNA clones specifying sandbar shark constant regions." Proceedings of the National Academy of Sciences 86(24): 9961-9965. (PubMed)

304. Schluter, S. F. and Marchalonis, J. J. (2003). "Cloning of shark RAG2 and characterization of the RAG1/RAG2 gene locus." FASEB Journal 17(3): 470-472. (PubMed)

305. Shamblott, M. J. and Litman, G. W. (1989). "Genomic organization and sequences of immunoglobulin light chain genes in a primitive vertebrate suggest coevolution of immunoglobulin gene organization." The EMBO Journal 8(12): 3733-3739. (PubMed)

306. Shankey, T. V. and Clem, L. W. (1980). "Phylogeny of immunoglobulin structure and function. IX. Intramolecular heterogeneity of shark 19S IgM antibodies to the dinitrophenyl hapten." Journal of Immunology 125(6): 2690-2698. (PubMed)

307. Shankey, T. V. and Clem, L. W. (1980). "Phylogeny of immunoglobulin structure and function--VIII. Intermolecular heterogeneity of shark 19S IgM antibodies to pneumococcal polysaccharide." Molecular Immunology 17(3): 365-375. (PubMed)

308. Shen, S. X., Bernstein, R. M., Schluter, S. F. and Marchalonis, J. J. (1996). "Heavy-chain variable regions in carcharhine sharks: development of a comprehensive model for the evolution of VH domains among the gnathanstomes." Immunology and Cell Biology 74(4): 357-364. (PubMed)

309. Síma, P. and Vetvicka, V. (1990). Evolution of Immune Reactions. Boca Raton, CRC Press. (Library | Amazon | Google Print)

310. Síma, P. and Vetvicka, V. (1992). "Evolution of Immune Accessory Functions." Immune System Accessory Cells. Edited by L. Fornusek and P. Síma. Boca Raton, CRC Press: 1-55. (Library | Amazon | Google Print)

311.* Síma, P. and Vetvicka, V. (1993). "Evolution of immune reactions." Critical Reviews in Immunology 13(2): 83-114. (PubMed)

312. Smith, L. C., Azumi, K. and Nonaka, M. (1999). "Complement systems in invertebrates. The ancient alternative and lectin pathways." Immunopharmacology 42(1-3): 107-120. (PubMed)

313. Smith, L. C., Clow, L. A. and Terwilliger, D. P. (2001). "The ancestral complement system in sea urchins." Immunological Reviews 180: 16-34. (PubMed)

314. Smith, L. C., Shih, C. S. and Dachenhausen, S. G. (1998). "Coelomocytes express SpBf, a homologue of factor B, the second component in the sea urchin complement system." Journal of Immunology 161(12): 6784-6793. (PubMed)

315. Smith, S. L. (1998). "Shark complement: an assessment." Immunological Reviews 166: 67-78. (PubMed)

316. Sottrup-Jensen, L., Stepanik, T. M., Kristensen, T., Lonblad, P. B., Jones, C. M., Wierzbicki, D. M., Magnusson, S., Domdey, H., Wetsel, R. A., Lundwall, A. and et al. (1985). "Common evolutionary origin of alpha 2-macroglobulin and complement components C3 and C4." Proceedings of the National Academy of Sciences 82(1): 9-13. (PubMed)

317. Spanopoulou, E., Zaitseva, F., Wang, F. H., Santagata, S., Baltimore, D. and Panayotou, G. (1996). "The homeodomain region of Rag-1 reveals the parallel mechanisms of bacterial and V(D)J recombination." Cell 87(2): 263-276. (PubMed)

318. Stavnezer, J. and Amemiya, C. T. (2004). "Evolution of isotype switching." Seminars in Immunology 16(4): 257-275. (Google Scholar | DOI | Journal | PubMed)

319. Stewart, J. (1992). "Immunoglobulins did not arise in evolution to fight infection." Immunology Today 13(10): 396-399; discussion 399-400. (PubMed)

320.* Stewart, J. (1994). The Primordial VRM System and the Evolution of Vertebrate Immunity. Austin, R. G. Landes. (Library | Amazon | Google Print)

321. Sun, S. C., Lindstrom, I., Boman, H. G., Faye, I. and Schmidt, O. (1990). "Hemolin: an insect-immune protein belonging to the immunoglobulin superfamily." Science 250(4988): 1729-1732. (PubMed)

322. Sunyer, J. O., Boshra, H. and Li, J. (2005). "Evolution of anaphylatoxins, their diversity and novel roles in innate immunity: insights from the study of fish complement." Veternary Immunology and Immunopathology 108(1-2): 77-89. (PubMed)

323. Sunyer, J. O., Boshra, H., Lorenzo, G., Parra, D., Freedman, B. and Bosch, N. (2003). "Evolution of complement as an effector system in innate and adaptive immunity." Immunologic Research 27(2-3): 549-564. (PubMed)

324. Sunyer, J. O. and Lambris, J. D. (1998). "Evolution and diversity of the complement system of poikilothermic vertebrates." Immunological Reviews 166: 39-57. (PubMed)

325. Sunyer, J. O., Tort, L. and Lambris, J. D. (1997). "Structural C3 diversity in fish: characterization of five forms of C3 in the diploid fish Sparus aurata." Journal of Immunology 158(6): 2813-2821. (PubMed)

326. Sunyer, J. O., Zarkadis, I. K. and Lambris, J. D. (1998). "Complement diversity: a mechanism for generating immune diversity?" Immunology Today 19(11): 519-523. (PubMed)

327. Suzuki, M. M., Satoh, N. and Nonaka, M. (2002). "C6-like and C3-like molecules from the cephalochordate, amphioxus, suggest a cytolytic complement system in invertebrates." Journal of Molecular Evolution 54(5): 671-679. (PubMed)

328. Suzuki, T., Shin, I. T., Fujiyama, A., Kohara, Y. and Kasahara, M. (2005). "Hagfish leukocytes express a paired receptor family with a variable domain resembling those of antigen receptors." Journal of Immunology 174(5): 2885-2891. (PubMed)

329. Suzuki, T., Shin, I. T., Kohara, Y. and Kasahara, M. (2004). "Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes." Developmental and Comparative Immunology 28(10): 993-1003. (PubMed)

330. Takahashi, H., Ishikawa, G., Ueki, K., Azumi, K. and Yokosawa, H. (1997). "Cloning and tyrosine phosphorylation of a novel invertebrate immunocyte protein containing immunoreceptor tyrosine-based activation motifs." Journal of Biological Chemistry 272(51): 32006-32010. (PubMed)

331. Terado, T., Nonaka, M. I., Nonaka, M. and Kimura, H. (2002). "Conservation of the modular structure of complement factor I through vertebrate evolution." Developmental and Comparative Immunology 26(5): 403-413. (PubMed)

332. Thompson, C. B. (1995). "New insights into V(D)J recombination and its role in the evolution of the immune system." Immunity 3(5): 531-539. (Google Scholar | DOI | Journal | PubMed)

333. Tonegawa, S. (1983). "Somatic generation of antibody diversity." Nature 302(5909): 575-581. (PubMed)

334. Uinuk-Ool, T., Mayer, W. E., Sato, A., Dongak, R., Cooper, M. D. and Klein, J. (2002). "Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes." Proceedings of the National Academy of Sciences 99(22): 14356-14361. (Google Scholar | DOI | Journal | PubMed)

335. Vaandrager, J.-W., Schuuring, E., Philippo, K. and Kluin, P. M. (2000). "V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma." Blood 96(5): 1947-1952. (Google Scholar | Journal | PubMed)

336. van den Berg, T. K., Yoder, J. A. and Litman, G. W. (2004). "On the origins of adaptive immunity: innate immune receptors join the tale." Trends in Immunology 25(1): 11-16. (PubMed)

337. van Gent, D. C., McBlane, J. F., Ramsden, D. A., Sadofsky, M. J., Hesse, J. E. and Gellert, M. (1995). "Initiation of V(D)J recombination in a cell-free system." Cell 81(6): 925-934. (PubMed)

338. van Gent, D. C., Mizuuchi, K. and Gellert, M. (1996). "Similarities between initiation of V(D)J recombination and retroviral integration." Science 271(5255): 1592-1594. (Google Scholar | Journal | JSTOR | PubMed)

339. van Gent, D. C., Ramsden, D. A. and Gellert, M. (1996). "The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination." Cell 85(1): 107-113. (PubMed)

340. Vasta, G. R. and Marchalonis, J. J. (1987). "Lectins from protochordates as putative recognition molecules." Progress in Clinical and Biological Research 233: 23-32. (PubMed)

341. Vasta, G. R., Marchalonis, J. J. and Kohler, H. (1984). "Invertebrate recognition protein cross-reacts with an immunoglobulin idiotype." Journal of Experimental Medicine 159(4): 1270-1276. (PubMed)

342. Vetvicka, V. and Síma, P. (1998). Evolutionary Mechanisms of Defense Reactions. Basel, Birkhäuser Verlag. (Library | Amazon | Google Print)

343. Vetvicka, V., Síma, P., Cooper, E. L., Bilej, M. and Roch, P. (1994). Immunology of Annelids. Boca Raton, CRC Press. (Library | Amazon | Google Print)

344. Vilmos, P. and Kurucz, E. (1998). "Insect immunity: evolutionary roots of the mammalian innate immune system." Immunology Letters 62(2): 59-66. (PubMed)

345. Vyazov, O. E. and Murashova, A. I. (1962). "Attempt at a comparative evolutionary approach to the study of the mechanism of antibody formation. I. Study of humoral immunity factors in invertebrates." Folia Microbiologica (Praha) 7: 93-97. (PubMed)

346. Vyazov, O. E. and Murashova, A. I. (1962). "Attempt at a comparative evolutionary approach to the study of the mechanism of antibody formation. II. The problem of the mechanism of autoantibody formation." Folia Microbiologica (Praha) 7: 98-103. (PubMed)

347. Wagner, C. and Hansch, G. M. (2006). "Receptors for complement C3 on T-lymphocytes: relics of evolution or functional molecules?" Molecular Immunology 43(1-2): 22-30. (DOI | Journal | PubMed)

348. Warr, G. W. and Cohen, N., eds. (1991). Phylogenesis of Immune Functions. Boca Raton, CRC Press. (Library | Amazon | Google Print)

349. Warr, G. W., DeLuca, D. and Marchalonis, J. J. (1976). "Phylogenetic origins of immune recognition: lymphocyte surface immunoglobulins in the goldfish, Carassius auratus." Proceedings of the National Academy of Sciences 73(7): 2476-2480. (PubMed)

350. Warr, G. W. and Marchalonis, J. J. (1978). "Specific immune recognition by lymphocytes: an evolutionary perspective." Quarterly Review of Biology 53(3): 225-241. (PubMed)

351. Weissman, I. L., Saito, Y. and Rinkevich, B. (1990). "Allorecognition histocompatibility in a protochordate species: is the relationship to MHC somatic or structural?" Immunological Reviews 113: 227-241. (PubMed)

352. Xiao, Y., Hughes, A. L., Ando, J., Matsuda, Y., Cheng, J. F., Skinner-Noble, D. and Zhang, G. (2004). "A genome-wide screen identifies a single beta-defensin gene cluster in the chicken: implications for the origin and evolution of mammalian defensins." BMC Genomics 5(1): 56. (PubMed)

353. Xu, Y., Narayana, S. V. and Volanakis, J. E. (2001). "Structural biology of the alternative pathway convertase." Immunological Reviews 180: 123-135. (PubMed)

354. Yoshizaki, F. Y., Ikawa, S., Satake, M., Satoh, N. and Nonaka, M. (2005). "Structure and the evolutionary implication of the triplicated complement factor B genes of a urochordate ascidian, Ciona intestinalis." Immunogenetics 56(12): 930-942. (PubMed)

355. Zapata, A., Fange, R., Mattisson, A. and Villena, A. (1984). "Plasma cells in adult Atlantic hagfish, Myxine glutinosa." Cell and Tissue Research 235(3): 691-693. (PubMed)

356. Zarkadis, I. K., Mastellos, D. and Lambris, J. D. (2001). "Phylogenetic aspects of the complement system." Developmental and Comparative Immunology 25(8-9): 745-762. (Google Scholar | DOI | Journal | PubMed)

357. Zhou, L., Mitra, R., Atkinson, P. W., Hickman, A. B., Dyda, F. and Craig, N. L. (2004). "Transposition of hAT elements links transposable elements and V(D)J recombination." Nature 432: 995-1001. (Google Scholar | DOI | Journal | PubMed)


Full Bibliography: Chronological

1. Metchnikoff, E. (1891 [1968]). Lectures on the comparative pathology of inflammation; delivered at the Pasteur Institute in 1891. Dover, New York.

2. Vyazov, O. E. and Murashova, A. I. (1962). "Attempt at a comparative evolutionary approach to the study of the mechanism of antibody formation. I. Study of humoral immunity factors in invertebrates." Folia Microbiologica (Praha) 7: 93-97. (PubMed)

3. Vyazov, O. E. and Murashova, A. I. (1962). "Attempt at a comparative evolutionary approach to the study of the mechanism of antibody formation. II. The problem of the mechanism of autoantibody formation." Folia Microbiologica (Praha) 7: 98-103. (PubMed)

4. Burnet, F. M. (1963). "The Evolution of Bodily Defence." Medical Journal of Australia 15: 817-821. (PubMed)

5. Finstad, J., Papermaster, B. W. and Good, R. A. (1964). "Evolution of the Immune Response. 2. Morphologic Studies on the Origin of the Thymus and Organized Lymphoid Tissue." Laboratory Investigation; a journal of technical methods and pathology 13: 490-512. (PubMed)

6. Good, R. A. and Papermaster, B. W. (1964). "Ontogeny and Phylogeny of Adaptive Immunity." Advances in Immunology 27: 1-115. (PubMed)

7. Papermaster, B. W., Condie, R. M., Finstad, J. and Good, R. A. (1964). "Evolution of the Immune Response. 1. The Phylogenetic Development of Adaptive Immunologic Responsiveness in Vertebrates." Journal of Experimental Medicine 119: 105-130. (PubMed)

8. Marchalonis, J. and Edelman, G. M. (1965). "Phylogenetic origins of antibody structure. I. Multichain structure of immunoglobulins in the smooth dogfish (Mustelus canis)." Journal of Experimental Medicine 122(3): 601-618. (PubMed)

9. Clawson, C. C., Finstad, J. and Good, R. A. (1966). "Evolution of the immune response. 5. Electron microscopy of plasma cells and lymphoid tissue of the paddlefish." Laboratory Investigation; a journal of technical methods and pathology 15(12): 1830-1847. (PubMed)

10. Marchalonis, J. and Edelman, G. M. (1966). "Phylogenetic origins of antibody structure. II. Immunoglobulins in the primary immune response of the bullfrog, Rana catesbiana." Journal of Experimental Medicine 124(5): 901-913. (PubMed)

11. Clem, I. W., De Boutaud, F. and Sigel, M. M. (1967). "Phylogeny of immunoglobulin structure and function. II. Immunoglobulins of the nurse shark." Journal of Immunology 99(6): 1226-1235. (PubMed)

12. Clem, L. W. and Small, P. A., Jr. (1967). "Phylogeny of immunoglobulin structure and function. I. Immunoglobulins of the lemon shark." Journal of Experimental Medicine 125(5): 893-920. (PubMed)

13. Burnet, F. M. (1968). "Evolution of the immune process in vertebrates." Nature 218(140): 426-430. (DOI | Journal | PubMed)

14. Marchalonis, J. J. and Edelman, G. M. (1968). "Phylogenetic origins of antibody structure. 3. Antibodies in the primary immune response of the sea lamprey, Petromyzon marinus." Journal of Experimental Medicine 127(5): 891-914. (PubMed)

15. Perey, D. Y., Finstad, J., Pollara, B. and Good, R. A. (1968). "Evolution of the immune response. 6. First and second set skin homograft rejections in primitive fishes." Laboratory Investigation; a journal of technical methods and pathology 19(6): 591-597. (PubMed)

16. Burnet, F. M. (1969). "The evolution of adaptive immunity in vertebrates." Acta Pathologica, Microbiologica et Immunologica Scandinavica 76(1): 1-11. (PubMed)

17. Burnet, F. M. (1970). "A certain symmetry: histocompatibility antigens compared with immunocyte receptors." Nature 226(5241): 123-126. (DOI | Journal | PubMed)

18. Clem, L. W. and Small, P. A., Jr. (1970). "Phylogeny of immunoglobulin structure and function. V. Valences and association constants of teleost antibodies to a haptenic determinant." Journal of Experimental Medicine 132(3): 385-400. (PubMed)

19. Litman, G. W., Finstad, F. J., Howell, J., Pollara, B. W. and God, R. A. (1970). "The evolution of the immune response. 3. Structural studies of the lamprey immuoglobulin." Journal of Immunology 105(5): 1278-1285. (PubMed)

20. Pollara, B., Litman, G. W., Finstad, J., Howell, J. and Good, R. A. (1970). "The evolution of the immune response. 7. Antibody to human "O" cells and properties of the immunoglobulin in lamprey." Journal of Immunology 105(3): 738-745. (PubMed)

21. Anonymous (1971). "A Wise Cell Knows Which its Parent." Nature 232(5308): 219-220. (DOI | Journal)

22. Burnet, F. M. (1971). "Self-recognition in colonial marine forms and flowering plants in relation to the evolution of immunity." Nature 232(5308): 230-235. (Google Scholar | DOI | Journal | PubMed)

23. Chartrand, S. L., Litman, G. W., Lapointe, N., Good, R. A. and Frommel, D. (1971). "The evolution of the immune response. 12. The immunoglobulins of the turtle. Molecular requirements for biologic activity of 5." Journal of Immunology 107(1): 1-11. (PubMed)

24. Clem, L. W. (1971). "Phylogeny of immunoglobulin structure and function. IV. Immunoglobulins of the giant grouper, Epinephelus itaira." Journal of Biological Chemistry 246(1): 9-15. (PubMed)

25. Frommel, D., Litman, G. W., Chartrand, S. L., Seal, U. S. and Good, R. A. (1971). "Carbohydrate composition in the evolution of the immunoglobulins." Immunochemistry 8(6): 573-577. (PubMed)

26. Frommel, D., Litman, G. W., Finstad, J. and Good, R. A. (1971). "The evolution of the immune response. 11. The immunoglobulins of the horned shark, Heterodontus francisci: purification, characterization and structural requirement for antibody activity." Journal of Immunology 106(5): 1234-1243. (PubMed)

27. Litman, G. W., Frommel, D., Finstad, J. and Good, R. A. (1971). "Evolution of the immune response. 10. Immunoglobulins of the bowfin: subunit nature." Journal of Immunology 107(3): 881-888. (PubMed)

28. Litman, G. W., Frommel, D., Rosenberg, A. and Good, R. A. (1971). "Circular dichroic analysis of immunoglobulins in phylogenetic perspective." Biochimica et Biophysica Acta 236(3): 647-654. (PubMed)

29. Litman, G. W., Fromme, D., Chartrand, S. L., Finstad, J. and Good, R. A. (1971). "Significance of heavy chain mass and antigenic relationship in immunoglobulin evolution." Immunochemistry 8(4): 345-349. (PubMed)

30. Litman, G. W., Frommel, D., Finstad, J. and Good, R. A. (1971). "The evolution of the immune reponse. 9. Immunoglobulins of the bowfin: purification and characterization." Journal of Immunology 106(3): 747-754. (PubMed)

31. Litman, G. W., Rosenberg, A., Frommel, D., Pollara, B., Finstad, J. and Good, R. A. (1971). "Biophysical studies of the immunoglobulins. The circular dichroic spectra of the immunoglobulins--a phylogenetic comparison." International Archives of Allergy and Immunology 40(4-5): 551-575. (PubMed)

32. Finstad, C. L., Litman, G. W., Finstad, J. and Good, R. A. (1972). "The evolution of the immune response. 13. The characterization of purified erythrocyte agglutinins from two invertebrate species." Journal of Immunology 108(6): 1704-1711. (PubMed)

33. Leslie, G. A. and Clem, L. W. (1972). "Phylogeny of immunoglobulin structure and function. VI. 17S, 7.5S and 5.7S anti-DNP of the turtle, Pseudamys scripta." Journal of Immunology 108(6): 1656-1664. (PubMed)

34. Burnet, F. M. (1973). "Multiple polymorphism in relation to histocompatibility antigens." Nature 245(5425): 359-361. (DOI | Journal | PubMed)

35. Hildemann, W. H. and Reddy, A. L. (1973). "Phylogeny of immune responsiveness: marine invertebrates." Federation Proceedings 32(12): 2188-2194. (PubMed)

36. Marchalonis, J. J. and Cone, R. E. (1973). "The phylogenetic emergence of vertebrate immunity." Australian Journal of Experimental Biology and Medical Science 51(4): 461-488. (PubMed)

37. Hildemann, W. H. (1974). "Phylogeny of immune responsiveness in invertebrates." Life Sciences 14(4): 605-614. (PubMed)

38. Clem, L. W. and McLean, W. E. (1975). "Phylogeny of immunoglobulin structure and function. VII. Monomeric and tetrameric immunoglobulins of the margate, a marine teleost fish." Immunology 29(4): 791-799. (PubMed)

39. Litman, G. W. (1975). "Relationship between structure and function of lower vertebrate immunoglobulins." Advances in Experimental Medicine and Biology 64: 217-228. (PubMed)

40. Merz, D. C., Finstad, C. L., Litman, G. W. and Good, R. A. (1975). "Aspects of vertebrate immunoglobulin evolution. Constancy in light chain electrophoretic behavior." Immunochemistry 12(6-7): 499-504. (PubMed)

41. Makela, O., Koskimies, S. and Karjalainen, K. (1976). "Possible evolution of acquired immunity from self-recognition structures." Scandinavian Journal of Immunology 5(4): 305-310. (PubMed)

42. Marchalonis, J. J. (1976). Immunity in Evolution. Cambridge, Mass., Harvard University Press. (Library | Amazon | Google Print)

43. Warr, G. W., DeLuca, D. and Marchalonis, J. J. (1976). "Phylogenetic origins of immune recognition: lymphocyte surface immunoglobulins in the goldfish, Carassius auratus." Proceedings of the National Academy of Sciences 73(7): 2476-2480. (PubMed)

44. Klapper, D. G. and Clem, L. W. (1977). "Phylogeny of immunoglobulin structure and function; characterization of the cysteine-containing peptide involved in the pentamerization of shark IgM." Developmental and Comparative Immunology 1(2): 81-91. (PubMed)

45. Marchalonis, J. J., Decker, J. M., DeLuca, D., Moseley, J. M., Smith, P. and Warr, G. W. (1977). "Lymphocyte surface immunoglobulins: evolutionary origins and involvement in activation." Cold Spring Harbor Symposium on Quantitative Biology 41 Pt 1: 261-273. (Journal | PubMed)

46. Ruben, L. N., Warr, G. W., Decker, J. M. and Marchalonis, J. J. (1977). "Phylogenetic origins of immune recognition: lymphoid heterogeneity and the hapten/carrier effect in the goldfish, Carassius auratus." Cellular Immunology 31(2): 266-283. (PubMed)

47. DeLuca, D., Warr, G. W. and Marchalonis, J. J. (1978). "Phylogenetic origins of immune recognition: lymphocyte surface immunoglobulins and antigen binding in the genus Carassius (Teleostii)." European Journal of Immunology 8(7): 525-530. (PubMed)

48. Marchalonis, J. J. and Warr, G. W. (1978). "Phylogenetic origins of immune recognition: naturally occurring DNP-binding molecules in chordate sera and hemolymph." Developmental and Comparative Immunology 2(3): 443-459. (PubMed)

49. Marchalonis, J. J., Warr, G. W. and Ruben, L. N. (1978). "Evolutionary immunobiology and the problem of the T-cell receptor." Developmental and Comparative Immunology 2(2): 203-218. (PubMed)

50. Warr, G. W. and Marchalonis, J. J. (1978). "Specific immune recognition by lymphocytes: an evolutionary perspective." Quarterly Review of Biology 53(3): 225-241. (PubMed)

51. Lachmann, P. J. and Hobart, M. J. (1979). "The genetics of the complement system." Ciba Foundation Symposium(66): 231-250. (PubMed)

52. Sakano, H., Hüppi, K., Heinrich, G. and Tonegawa, S. (1979). "Sequences at the somatic recombination sites of immunoglobulin light-chain genes." Nature 280(6): 288-294. (Google Scholar | DOI | Journal | PubMed)

53. Litman, G. W., Scheffel, C. and Gerber-Jenson, B. (1980). "Immunoglobulin diversity in the phylogenetically primitive shark, Heterodontus francisci. Suggested lack of structural variation between light chains isolated from different animals." Journal of Immunogenetics 7(3): 197-206. (PubMed)

54. Manning, M. J., ed. (1980). Phylogeny of Immunological Memory. Developments in Immunology. Amsterdam, Elsevier/North-Holland Biomedical Press. (Library | Amazon | Google Print)

55. Shankey, T. V. and Clem, L. W. (1980). "Phylogeny of immunoglobulin structure and function. IX. Intramolecular heterogeneity of shark 19S IgM antibodies to the dinitrophenyl hapten." Journal of Immunology 125(6): 2690-2698. (PubMed)

56. Shankey, T. V. and Clem, L. W. (1980). "Phylogeny of immunoglobulin structure and function--VIII. Intermolecular heterogeneity of shark 19S IgM antibodies to pneumococcal polysaccharide." Molecular Immunology 17(3): 365-375. (PubMed)

57. Lobb, C. J. and Clem, L. W. (1981). "Phylogeny of immunoglobulin structure and function-XII. Secretory immunoglobulins in the bile of the marine teleost Archosargus probatocephalus." Molecular Immunology 18(7): 615-619. (PubMed)

58. Lobb, C. J. and Clem, L. W. (1981). "Phylogeny of immunoglobulin structure and function. XI. Secretory immunoglobulins in the cutaneous mucus of the sheepshead, Archosargus probatocephalus." Developmental and Comparative Immunology 5(4): 587-596. (PubMed)

59. Lobb, C. J. and Clem, W. (1981). "Phylogeny of immunoglobulin in structure and function-x. Humoral immunoglobulins of the sheepshead, Archosargus probatocephalus." Developmental and Comparative Immunology 5(2): 271-282. (PubMed)

60. Clem, L. W. and Leslie, G. A. (1982). "Phylogeny of immunoglobulin structure and function. XIV. Peptide map and amino acid composition studies of shark antibody light chains." Developmental and Comparative Immunology 6(2): 263-269. (PubMed)

61. Clem, L. W. and Leslie, G. A. (1982). "Phylogeny of immunoglobulin structure and function XV. Idiotypic analysis of shark antibodies." Developmental and Comparative Immunology 6(3): 463-472. (PubMed)

62. Du Pasquier, L. (1982). "Antibody diversity in lower vertebrates--why is it so restricted?" Nature 296(5855): 311-313. (PubMed)

63. Litman, G. W., Stolen, J. S., Sarvas, H. O. and Makela, O. (1982). "The range and fine specificity of the anti-hapten immune response: phylogenetic studies." Journal of Immunogenetics 9(6): 465-474. (PubMed)

64. Litman, G. W., Erickson, B. W., Lederman, L. and Makela, O. (1982). "Antibody response in Heterodontus." Molecular and Cellular Biochemistry 45(1): 49-57. (PubMed)

65. Quigley, J. P. and Armstrong, P. B. (1983). "An endopeptidase inhibitor found in Limulus plasma: an ancient form of alpha 2-macroglobulin." Annals of the New York Academy of Sciences 421: 119-124. (PubMed)

66. Tonegawa, S. (1983). "Somatic generation of antibody diversity." Nature 302(5909): 575-581. (PubMed)

67. Litman, G. W., Berger, L., Murphy, K., Litman, R., Podlaski, F., Hinds, K., Jahn, C. L., Dingerkus, G. and Erickson, B. W. (1984). "Phylogenetic diversification of immunoglobulin VH genes." Developmental and Comparative Immunology 8(3): 499-514. (PubMed)

68. Nonaka, M., Fujii, T., Kaidoh, T., Natsuume-Sakai, S., Yamaguchi, N. and Takahashi, M. (1984). "Purification of a lamprey complement protein homologous to the third component of the mammalian complement system." Journal of Immunology 133(6): 3242-3249. (PubMed)

69. Raison, R. L. and Hildemann, W. H. (1984). "Immunoglobulin-bearing blood leucocytes in the Pacific hagfish." Developmental and Comparative Immunology 8(1): 99-108. (PubMed)

70. Vasta, G. R., Marchalonis, J. J. and Kohler, H. (1984). "Invertebrate recognition protein cross-reacts with an immunoglobulin idiotype." Journal of Experimental Medicine 159(4): 1270-1276. (PubMed)

71. Zapata, A., Fange, R., Mattisson, A. and Villena, A. (1984). "Plasma cells in adult Atlantic hagfish, Myxine glutinosa." Cell and Tissue Research 235(3): 691-693. (PubMed)

72. Litman, G. W., Hinds, K., Berger, L., Murphy, K. and Litman, R. (1985). "Structure and organization of immunoglobulin VH genes in Heterodontus, a phylogenetically primitive shark." Developmental and Comparative Immunology 9(4): 749-758. (PubMed)

73. Litman, G. W., Berger, L., Murphy, K., Litman, R., Hinds, K. and Erickson, B. W. (1985). "Immunoglobulin VH gene structure and diversity in Heterodontus, a phylogenetically primitive shark." Proceedings of the National Academy of Sciences 82(7): 2082-2086. (PubMed)

74. Quigley, J. P. and Armstrong, P. B. (1985). "A homologue of alpha 2-macroglobulin purified from the hemolymph of the horseshoe crab Limulus polyphemus." Journal of Biological Chemistry 260(23): 12715-12719. (PubMed)

75. Sottrup-Jensen, L., Stepanik, T. M., Kristensen, T., Lonblad, P. B., Jones, C. M., Wierzbicki, D. M., Magnusson, S., Domdey, H., Wetsel, R. A., Lundwall, A. and et al. (1985). "Common evolutionary origin of alpha 2-macroglobulin and complement components C3 and C4." Proceedings of the National Academy of Sciences 82(1): 9-13. (PubMed)

76. Gilbertson, P., Wotherspoon, J. and Raison, R. L. (1986). "Evolutionary development of lymphocyte heterogeneity: leucocyte subpopulations in the Pacific hagfish." Developmental and Comparative Immunology 10(1): 1-10. (PubMed)

77. Hinds, K. R. and Litman, G. W. (1986). "Major reorganization of immunoglobulin VH segmental elements during vertebrate evolution." Nature 320(6062): 546-549. (PubMed)

78. Klein, J. (1986). "Evolution of Mhc." Natural History of the Major Histocompatibility Complex. New York, John Wiley & Sons: 715-762. (Library | Google Print)

79. Kelsoe, G. and Schulze, D. H., eds. (1987). Evolution and Vertebrate Immunity: The Antigen-Receptor and MHC Gene Families. Austin, University of Texas Press. (Library | Amazon | Google Print)

80. Litman, G. W., Hinds, K. R., Litman, R. T. and Kokubu, F. (1987). "The early phylogenetic origin of antibody gene structure and function." Progress in Clinical and Biological Research 233: 1-11. (PubMed)

81. Vasta, G. R. and Marchalonis, J. J. (1987). "Lectins from protochordates as putative recognition molecules." Progress in Clinical and Biological Research 233: 23-32. (PubMed)

82. Kokubu, F., Litman, R., Shamblott, M. J., Hinds, K. and Litman, G. W. (1988). "Diverse organization of immunoglobulin VH gene loci in a primitive vertebrate." The EMBO Journal 7(11): 3413-3422. (PubMed)

83. Grossberger, D., Marcuz, A., Du Pasquier, L. and Lambris, J. D. (1989). "Conservation of structural and functional domains in complement component C3 of Xenopus and mammals." Proceedings of the National Academy of Sciences 86(4): 1323-1327. (PubMed)

84. Langman, R. E. (1989). The immune system: Evolutionary principles guide our understanding of this complex biological defense system. San Diego, Academic Press, Inc.

85. Marchalonis, J. J. and Schluter, S. F. (1989). "Evolution of variable and constant domains and joining segments of rearranging immunoglobulins." FASEB Journal 3(13): 2469-2479. (PubMed)

86. Marchalonis, J. J. and Schluter, S. F. (1989). "Immunoproteins in evolution." Developmental and Comparative Immunology 13(4): 285-301. (PubMed)

87. Reinisch, C. L. and Litman, G. W. (1989). "Evolutionary immunobiology." Immunology Today 10(8): 278-281. (PubMed)

88. Schatz, D. G., Oettinger, M. A. and Baltimore, D. (1989). "The V(D)J recombination activating gene, RAG-1." Cell 59(6): 1035-1048. (PubMed)

89. Schluter, S. F., Hohman, V. S., Edmundson, A. B. and Marchalonis, J. J. (1989). "Evolution of immunoglobulin light chains: cDNA clones specifying sandbar shark constant regions." Proceedings of the National Academy of Sciences 86(24): 9961-9965. (PubMed)

90. Shamblott, M. J. and Litman, G. W. (1989). "Genomic organization and sequences of immunoglobulin light chain genes in a primitive vertebrate suggest coevolution of immunoglobulin gene organization." The EMBO Journal 8(12): 3733-3739. (PubMed)

91. Amemiya, C. T. and Litman, G. W. (1990). "Complete nucleotide sequence of an immunoglobulin heavy-chain gene and analysis of immunoglobulin gene organization in a primitive teleost species." Proceedings of the National Academy of Sciences 87(2): 811-815. (PubMed)

92. Farries, T. C., Steuer, K. L. and Atkinson, J. P. (1990). "Evolutionary implications of a new bypass activation pathway of the complement system." Immunology Today 11(3): 78-80. (PubMed)

93. Flajnik, M. F. and Du Pasquier, L. (1990). "The major histocompatibility complex of frogs." Immunological Reviews 113: 47-63. (PubMed)

94. Harding, F. A., Cohen, N. and Litman, G. W. (1990). "Immunoglobulin heavy chain gene organization and complexity in the skate, Raja erinacea." Nucleic Acids Research 18(4): 1015-1020. (PubMed)

95. Harvell, C. D. (1990). "The evolution of inducible defence." Parasitology 100 Suppl: S53-61. (PubMed)

96. Lawlor, D. A., Zemmour, J., Ennis, P. D. and Parham, P. (1990). "Evolution of Class-I MHC Genes and Proteins: From Natural Selection to Thymic Selection." Annual Review of Immunology 8: 23-63. (DOI | Journal | PubMed)

97. Marchalonis, J. J. and Schluter, S. F. (1990). "On the relevance of invertebrate recognition and defence mechanisms to the emergence of the immune response of vertebrates." Scandinavian Journal of Immunology 32(1): 13-20. (PubMed)

98. Oettinger, M. A., Schatz, D. G., Gorka, C. and Baltimore, D. (1990). "RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination." Science 248(4962): 1517-1523. (PubMed)

99. Síma, P. and Vetvicka, V. (1990). Evolution of Immune Reactions. Boca Raton, CRC Press. (Library | Amazon | Google Print)

100. Sun, S. C., Lindstrom, I., Boman, H. G., Faye, I. and Schmidt, O. (1990). "Hemolin: an insect-immune protein belonging to the immunoglobulin superfamily." Science 250(4988): 1729-1732. (PubMed)

101. Weissman, I. L., Saito, Y. and Rinkevich, B. (1990). "Allorecognition histocompatibility in a protochordate species: is the relationship to MHC somatic or structural?" Immunological Reviews 113: 227-241. (PubMed)

102.* Farries, T. C. and Atkinson, J. P. (1991). "Evolution of the complement system." Immunology Today 12(9): 295-300. (PubMed)

103. Flajnik, M. F., Canel, C., Kramer, J. and Kasahara, M. (1991). "Evolution of the major histocompatibility complex: molecular cloning of major histocompatibility complex class I from the amphibian Xenopus." Proceedings of the National Academy of Sciences 88(2): 537-541. (PubMed)

104. Flajnik, M. F., Canel, C., Kramer, J. and Kasahara, M. (1991). "Which came first, MHC class I or class II?" Immunogenetics 33(5-6): 295-300. (PubMed)

105. Hendrickson, E. A., Qin, X. Q., Bump, E. A., Schatz, D. G., Oettinger, M. and Weaver, D. T. (1991). "A link between double-strand break-related repair and V(D)J recombination: the scid mutation." Proceedings of the National Academy of Sciences 88(10): 4061-4065. (PubMed)

106. Litman, G. W., Amemiya, C. T., Harding, F. A., Haire, R. N., Hinds, K. R., Litman, R. T., Ohta, Y., Shamblott, M. J. and Varner, J. A. (1991). "Evolutionary development of immunoglobulin gene diversity." Advances in Experimental Medicine and Biology 292: 11-17. (PubMed)

107. Warr, G. W. and Cohen, N., eds. (1991). Phylogenesis of Immune Functions. Boca Raton, CRC Press. (Library | Amazon | Google Print)

108. Bang, D. D., Verhage, R., Goosen, N., Brouwer, J. and van de Putte, P. (1992). "Molecular cloning of RAD16, a gene involved in differential repair in Saccharomyces cerevisiae." Nucleic Acids Research 20(15): 3925-3931. (PubMed)

109. Dreyfus, D. H. (1992). "Evidence suggesting an evolutionary relationship between transposable elements and immune system recombination sequences." Molecular Immunology 29(6): 807-810. (Google Scholar | DOI | Journal | PubMed)

110.* Du Pasquier, L. (1992). "Origin and evolution of the vertebrate immune system." Acta Pathologica, Microbiologica et Immunologica Scandinavica 100: 383. (Google Scholar)

111. Hanley, P. J., Hook, J. W., Raftos, D. A., Gooley, A. A., Trent, R. and Raison, R. L. (1992). "Hagfish humoral defense protein exhibits structural and functional homology with mammalian complement components." Proceedings of the National Academy of Sciences 89(17): 7910-7914. (PubMed)

112. Kasahara, M., Vazquez, M., Sato, K., McKinney, E. C. and Flajnik, M. F. (1992). "Evolution of the major histocompatibility complex: isolation of class II A cDNA clones from the cartilaginous fish." Proceedings of the National Academy of Sciences 89(15): 6688-6692. (PubMed)

113. Langman, R. E. and Cohn, M. (1992). "What is the selective pressure that maintains the gene loci encoding the antigen receptors of T and B cells? A hypothesis." Immunology and Cell Biology 70 ( Pt 6): 397-404. (PubMed)

114. Litman, G. W., Haire, R. N., Hinds, K. R., Amemiya, C. T., Rast, J. P. and Hulst, M. (1992). "Evolutionary development of the B-cell repertoire." Annals of the New York Academy of Sciences 651: 360-368. (PubMed)

115. Nonaka, M. and Takahashi, M. (1992). "Complete complementary DNA sequence of the third component of complement of lamprey. Implication for the evolution of thioester containing proteins." Journal of Immunology 148(10): 3290-3295. (PubMed)

116. Roth, D. B., Nakajima, P. B., Menetski, J. P., Bosma, M. J. and Gellert, M. (1992). "V(D)J recombination in mouse thymocytes: double-strand breaks near T cell receptor delta rearrangement signals." Cell 69(1): 41-53. (PubMed)

117. Schatz, D. G., Oettinger, M. A. and Schlissel, M. S. (1992). "V(D)J recombination: molecular biology and regulation." Annual Review of Immunology 10: 359-383. (PubMed)

118. Síma, P. and Vetvicka, V. (1992). "Evolution of Immune Accessory Functions." Immune System Accessory Cells. Edited by L. Fornusek and P. Síma. Boca Raton, CRC Press: 1-55. (Library | Amazon | Google Print)

119. Stewart, J. (1992). "Immunoglobulins did not arise in evolution to fight infection." Immunology Today 13(10): 396-399; discussion 399-400. (PubMed)

120. Amemiya, C. T., Ohta, Y., Litman, R. T., Rast, J. P., Haire, R. N. and Litman, G. W. (1993). "VH gene organization in a relict species, the coelacanth Latimeria chalumnae: evolutionary implications." Proceedings of the National Academy of Sciences 90(14): 6661-6665. (PubMed)

121. Du Pasquier, L. (1993). "Phylogeny of B-cell development." Current Opinion in Immunology 5(2): 185-193. (PubMed)

122. Hinds-Frey, K. R., Nishikata, H., Litman, R. T. and Litman, G. W. (1993). "Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity." Journal of Experimental Medicine 178(3): 815-824. (PubMed)

123. Kasahara, M., McKinney, E. C., Flajnik, M. F. and Ishibashi, T. (1993). "The evolutionary origin of the major histocompatibility complex: polymorphism of class II alpha chain genes in the cartilaginous fish." European Journal of Immunology 23(9): 2160-2165. (PubMed)

124. Litman, G. W., Rast, J. P., Shamblott, M. J., Haire, R. N., Hulst, M., Roess, W., Litman, R. T., Hinds-Frey, K. R., Zilch, A. and Amemiya, C. T. (1993). "Phylogenetic diversification of immunoglobulin genes and the antibody repertoire." Molecular Biology and Evolution 10(1): 60-72. (PubMed)

125. Sato, K., Flajnik, M. F., Du Pasquier, L., Katagiri, M. and Kasahara, M. (1993). "Evolution of the MHC: isolation of class II beta-chain cDNA clones from the amphibian Xenopus laevis." Journal of Immunology 150(7): 2831-2843. (PubMed)

126.* Síma, P. and Vetvicka, V. (1993). "Evolution of immune reactions." Critical Reviews in Immunology 13(2): 83-114. (PubMed)

127.* Bartl, S., Baltimore, D. and Weissman, I. L. (1994). "Molecular evolution of the vertebrate immune system." Proceedings of the National Academy of Sciences 91(23): 10769-10770. (Google Scholar | Journal | JSTOR | PubMed)

128. Beck, G., Cooper, E. L., Habicht, G. S. and Marchalonis, J. J., eds. (1994). Primordial Immunity: Foundations for the Vertebrate Immune System. New York, The New York Academy of Sciences. (Library | PubMed | Publisher | Amazon | Google Print)

129. Davidson, E. H. (1994). "Stepwise Evolution of Major Functional Systems in Vertebrates, Including the Immune System." Phylogenetic Perspectives in Immunity: The Insect Host Defense. Edited by J. A. Hoffman, C. A. Janeway and S. Natori. Austin, R.G. Landes Company: 133-142. (Library | Amazon | Google Print)

130. Dodds, A. W. (1994). "Molecular and Phylogenetic Aspects of the Complement System." Phylogenetic Perspectives in Immunity: The Insect Host Defense. Edited by J. A. Hoffman, C. A. Janeway and S. Natori. Austin, R.G. Landes Company: 143-155. (Library | Amazon | Google Print)

131. Hoffman, J. A., Janeway, C. A. and Natori, S., eds. (1994). Phylogenetic Perspectives in Immunity: The Insect Host Defense. Austin, R. G. Landes Company. (Library | Amazon | Google Print)

132. Iwanaga, S., Kawabata, S.-i., Miura, Y., Seki, N., Shigenaga, T. and Muta, T. (1994). "Clotting Cascade in the Immune Response of Horseshoe Crab." Phylogenetic Perspectives in Immunity: The Insect Host Defense. Edited by J. A. Hoffman, C. A. Janeway and S. Natori. Austin, R.G. Landes Company: 79-96. (Library | Amazon | Google Print)

133. Lewis, S. M. (1994). "The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses." Advances in Immunology 56: 27-150. (PubMed)

134. Marchalonis, J. J., Hohman, V. S., Kaymaz, H., Schluter, S. F. and Edmundson, A. B. (1994). "Cell Surface Recognition and the Immunoglobulin Superfamily." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 20-33. (Library | PubMed | Publisher | Google Print)

135. Marchalonis, J. J. and Schluter, S. F. (1994). "Development of an Immune System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 1-11. (Library | PubMed | Publisher | Google Print)

136. Newton, R. A., Raftos, D. A., Raison, R. L. and Geczy, C. L. (1994). "Chemotactic responses of hagfish (Vertebrata, Agnatha) leucocytes." Developmental and Comparative Immunology 18(4): 295-303. (PubMed)

137. Nonaka, M., Takahashi, M. and Sasaki, M. (1994). "Molecular cloning of a lamprey homologue of the mammalian MHC class III gene, complement factor B." Journal of Immunology 152(5): 2263-2269. (PubMed)

138. Ohno, S. (1994). "MHC Evolution and Development of a Recognition System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 13-19. (Library | PubMed | Publisher | Google Print)

139. Rast, J. P., Anderson, M. K., Ota, T., Litman, R. T., Margittai, M., Shamblott, M. J. and Litman, G. W. (1994). "Immunoglobulin light chain class multiplicity and alternative organizational forms in early vertebrate phylogeny." Immunogenetics 40(2): 83-99. (PubMed)

140. Rast, J. P. and Litman, G. W. (1994). "T-cell receptor gene homologs are present in the most primitive jawed vertebrates." Proceedings of the National Academy of Sciences 91(20): 9248-9252. (PubMed)

141. Saito, Y., Hirose, E. and Watanabe, H. (1994). "Allorecognition in compound ascidians." International Journal of Developmental Biology 38(2): 237-247. (PubMed)

142.* Stewart, J. (1994). The Primordial VRM System and the Evolution of Vertebrate Immunity. Austin, R. G. Landes. (Library | Amazon | Google Print)

143. Vetvicka, V., Síma, P., Cooper, E. L., Bilej, M. and Roch, P. (1994). Immunology of Annelids. Boca Raton, CRC Press. (Library | Amazon | Google Print)

144. Chu, T. W., Capossela, A., Coleman, R., Goei, V. L., Nallur, G. and Gruen, J. R. (1995). "Cloning of a new "finger" protein gene (ZNF173) within the class I region of the human MHC." Genomics 29(1): 229-239. (PubMed)

145. Hoffmann, J. A. (1995). "Innate immunity of insects." Current Opinion in Immunology 7(1): 4-10. (PubMed)

146. Kasahara, M., Flajnik, M. F., Ishibashi, T. and Natori, T. (1995). "Evolution of the major histocompatibility complex: a current overview." Transplant Immunology 3(1): 1-20. (PubMed)

147. Lindstrom-Dinnetz, I., Sun, S. C. and Faye, I. (1995). "Structure and expression of Hemolin, an insect member of the immunoglobulin gene superfamily." European Journal of Biochemistry 230(3): 920-925. (PubMed)

148. McBlane, J. F., van Gent, D. C., Ramsden, D. A., Romeo, C., Cuomo, C. A., Gellert, M. and Oettinger, M. A. (1995). "Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps." Cell 83(3): 387-395. (PubMed)

149. Thompson, C. B. (1995). "New insights into V(D)J recombination and its role in the evolution of the immune system." Immunity 3(5): 531-539. (Google Scholar | DOI | Journal | PubMed)

150. van Gent, D. C., McBlane, J. F., Ramsden, D. A., Sadofsky, M. J., Hesse, J. E. and Gellert, M. (1995). "Initiation of V(D)J recombination in a cell-free system." Cell 81(6): 925-934. (PubMed)

151. Beck, G. and Habicht, G. S. (1996). "Immunity and the invertebrates." Scientific American 275(5): 60-63, 66. (Journal)

152. Bernstein, R. M., Schluter, S. F., Bernstein, H. and Marchalonis, J. J. (1996). "Primordial emergence of the recombination activating gene 1 (RAG1): Sequence of the complete shark gene indicates homology to microbial integrases." Proceedings of the National Academy of Sciences 93(18): 9454-9459. (Google Scholar | Journal | JSTOR | PubMed)

153. Berstein, R. M., Schluter, S. F., Shen, S. and Marchalonis, J. J. (1996). "A new high molecular weight immunoglobulin class from the carcharhine shark: implications for the properties of the primordial immunoglobulin." Proceedings of the National Academy of Sciences 93(8): 3289-3293. (PubMed)

154. Difilippantonio, M. J., McMahan, C. J., Eastman, Q. M., Spanopoulou, E. and Schatz, D. G. (1996). "RAG1 mediates signal sequence recognition and recruitment of RAG2 in V(D)J recombination." Cell 87(2): 253-262. (PubMed)

155. Fearon, D. T. and Locksley, R. M. (1996). "The instructive role of innate immunity in the acquired immune response." Science 272(5258): 50-53. (JSTOR | PubMed)

156. Flajnik, M. F. (1996). "The immune system of ectothermic vertebrates." Veternary Immunology and Immunopathology 54(1-4): 145-150. (PubMed)

157. Gellert, M. (1996). "A new view of V(D)J recombination." Genes to Cells 1(3): 269-275. (PubMed)

158. Litman, G. W. (1996). "Sharks and the origins of vertebrate immunity." Scientific American 275(5): 67-71. (Journal | PubMed)

159. Marchalonis, J. J., Bernstein, R. M., Shen, S. X. and Schluter, S. F. (1996). "Emergence of the immunoglobulin family: conservation in protein sequence and plasticity in gene organization." Glycobiology 6(7): 657-663. (PubMed)

160. Muta, T. and Iwanaga, S. (1996). "The role of hemolymph coagulation in innate immunity." Current Opinion in Immunology 8(1): 41-47. (PubMed)

161. Shen, S. X., Bernstein, R. M., Schluter, S. F. and Marchalonis, J. J. (1996). "Heavy-chain variable regions in carcharhine sharks: development of a comprehensive model for the evolution of VH domains among the gnathanstomes." Immunology and Cell Biology 74(4): 357-364. (PubMed)

162. Spanopoulou, E., Zaitseva, F., Wang, F. H., Santagata, S., Baltimore, D. and Panayotou, G. (1996). "The homeodomain region of Rag-1 reveals the parallel mechanisms of bacterial and V(D)J recombination." Cell 87(2): 263-276. (PubMed)

163. van Gent, D. C., Ramsden, D. A. and Gellert, M. (1996). "The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination." Cell 85(1): 107-113. (PubMed)

164. van Gent, D. C., Mizuuchi, K. and Gellert, M. (1996). "Similarities between initiation of V(D)J recombination and retroviral integration." Science 271(5255): 1592-1594. (Google Scholar | Journal | JSTOR | PubMed)

165. Butler, J. E. (1997). "Immunoglobulin gene organization and the mechanism of repertoire development." Scandinavian Journal of Immunology 45(5): 455-462. (PubMed)

166. Gellert, M. (1997). "Recent advances in understanding V(D)J recombination." Advances in Immunology 64: 39-64. (PubMed)

167. Hagmann, M. (1997). "RAGged repair: what's new in V(D)J recombination." Biological Chemistry 378(8): 815-819. (PubMed)

168. Hughes, A. L. and Yeager, M. (1997). "Molecular evolution of the vertebrate immune system." BioEssays 19(9): 777-786. (Google Scholar | PubMed)

169. Ji, X., Azumi, K., Sasaki, M. and Nonaka, M. (1997). "Ancient origin of the complement lectin pathway revealed by molecular cloning of mannan binding protein-associated serine protease from a urochordate, the Japanese ascidian, Halocynthia roretzi." Proceedings of the National Academy of Sciences 94(12): 6340-6345. (Google Scholar | Journal | PubMed)

170. Klein, J. (1997). "Homology Between Immune Responses in Vertebrates and Invertebrates: Does it Exist?" Scandinavian Journal of Immunology 46(6): 558-564. (Google Scholar | Journal | PubMed)

171. Lewis, S. M. and Wu, G. E. (1997). "The origins of V(D)J recombination." Cell 88(2): 159-162. (Google Scholar | DOI | Journal | PubMed)

172. Medzhitov, R., Preston-Hurlburt, P. and Janeway, C. A., Jr. (1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity." Nature 388(6640): 394-397. (PubMed)

173. Medzhitov, R. and Janeway, C. A., Jr. (1997). "Innate immunity: the virtues of a nonclonal system of recognition." Cell 91(3): 295-298. (PubMed)

174. Rast, J. P., Anderson, M. K., Strong, S. J., Luer, C., Litman, R. T. and Litman, G. W. (1997). "alpha, beta, gamma, and delta T cell antigen receptor genes arose early in vertebrate phylogeny." Immunity 6(1): 1-11. (PubMed)

175. Schluter, S. F., Bernstein, R. M. and Marchalonis, J. J. (1997). "Molecular origins and evolution of immunoglobulin heavy-chain genes of jawed vertebrates." Immunology Today 18(11): 543-549. (Google Scholar | DOI | Journal | PubMed)

176. Sunyer, J. O., Tort, L. and Lambris, J. D. (1997). "Structural C3 diversity in fish: characterization of five forms of C3 in the diploid fish Sparus aurata." Journal of Immunology 158(6): 2813-2821. (PubMed)

177. Takahashi, H., Ishikawa, G., Ueki, K., Azumi, K. and Yokosawa, H. (1997). "Cloning and tyrosine phosphorylation of a novel invertebrate immunocyte protein containing immunoreceptor tyrosine-based activation motifs." Journal of Biological Chemistry 272(51): 32006-32010. (PubMed)

178. Agrawal, A., Eastman, Q. M. and Schatz, D. G. (1998). "Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system." Nature 394(6695): 744-751. (Google Scholar | DOI | Journal | PubMed)

179. Al-Sharif, W. Z., Sunyer, J. O., Lambris, J. D. and Smith, L. C. (1998). "Sea urchin coelomocytes specifically express a homologue of the complement component C3." Journal of Immunology 160(6): 2983-2997. (PubMed)

180. Cohn, M. (1998). "At the feet of the master: the search for universalities. Divining the evolutionary selection pressures that resulted in an immune system." Cytogenetics and Cell Genetics 80(1-4): 54-60. (DOI | Journal | PubMed)

181. Diaz, M. and Flajnik, M. F. (1998). "Evolution of somatic hypermutation and gene conversion in adaptive immunity." Immunological Reviews 162: 13-24. (PubMed)

182. Dodds, A. W. and Law, S. K. (1998). "The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin." Immunological Reviews 166: 15-26. (PubMed)

183. Du Pasquier, L., Wilson, M., Greenberg, A. S. and Flajnik, M. F. (1998). "Somatic mutation in ectothermic vertebrates: musings on selection and origins." Current Topics in Microbiology and Immunology 229: 199-216. (PubMed)

184. Flajnik M. (editor) (1998). "The immune systems of ectothermic vertebrates." Immunological Reviews 166: 1-384. (PubMed)

185. Hiom, K., Melek, M. and Gellert, M. (1998). "DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations." Cell 94(4): 463-470. (Google Scholar | DOI | Journal | PubMed)

186. Iwanaga, S. and Kawabata, S. (1998). "Evolution and phylogeny of defense molecules associated with innate immunity in horseshoe crab." Frontiers in Bioscience 3: D973-984. (PubMed)

187. Kennedy, A. K., Guhathakurta, A., Kleckner, N. and Haniford, D. B. (1998). "Tn10 transposition via a DNA hairpin intermediate." Cell 95(1): 125-134. (PubMed)

188. Lachmann, P. J. (1998). "Microbial immunology: a new mechanism for immune subversion." Current Biology 8(3): R99-R101. (PubMed)

189. Marchalonis, J. J., Schluter, S. F., Bernstein, R. M. and Hohman, V. S. (1998). "Antibodies of sharks: revolution and evolution." Immunological Reviews 166: 103-122. (PubMed)

190. Marchalonis, J. J., Schluter, S. F., Bernstein, R. M., Shen, S. and Edmundson, A. B. (1998). "Phylogenetic emergence and molecular evolution of the immunoglobulin family." Advances in Immunology 70: 417-506. (PubMed)

191. Marchalonis, J. J. and Schluter, S. F. (1998). "A stochastic model for the rapid emergence of specific vertebrate immunity incorporating horizontal transfer of systems enabling duplication and combinational diversification." Journal of Theoretical Biology 193(3): 429-444. (PubMed)

192. Matsunaga, T. and Rahman, A. (1998). "What brought the adaptive immune system to vertebrates?--The jaw hypothesis and the seahorse." Immunological Reviews 166: 177-186. (PubMed)

193. Matsushita, M., Endo, Y., Nonaka, M. and Fujita, T. (1998). "Complement-related serine proteases in tunicates and vertebrates." Current Opinion in Immunology 10(1): 29-35. (PubMed)

194. Medzhitov, R. and Janeway, C. A., Jr. (1998). "An ancient system of host defense." Current Opinion in Immunology 10(1): 12-15. (PubMed)

195. Plasterk, R. (1998). "Ragtime jumping." Nature 394(6695): 718-719. (Google Scholar | DOI | Journal | PubMed)

196. Rast, J. P. and Litman, G. W. (1998). "Towards understanding the evolutionary origins and early diversification of rearranging antigen receptors." Immunological Reviews 166: 79-86. (PubMed)

197. Sahu, A., Sunyer, J. O., Moore, W. T., Sarrias, M. R., Soulika, A. M. and Lambris, J. D. (1998). "Structure, functions, and evolution of the third complement component and viral molecular mimicry." Immunologic Research 17(1-2): 109-121. (PubMed)

198. Smith, L. C., Shih, C. S. and Dachenhausen, S. G. (1998). "Coelomocytes express SpBf, a homologue of factor B, the second component in the sea urchin complement system." Journal of Immunology 161(12): 6784-6793. (PubMed)

199. Smith, S. L. (1998). "Shark complement: an assessment." Immunological Reviews 166: 67-78. (PubMed)

200. Sunyer, J. O. and Lambris, J. D. (1998). "Evolution and diversity of the complement system of poikilothermic vertebrates." Immunological Reviews 166: 39-57. (PubMed)

201. Sunyer, J. O., Zarkadis, I. K. and Lambris, J. D. (1998). "Complement diversity: a mechanism for generating immune diversity?" Immunology Today 19(11): 519-523. (PubMed)

202. Vetvicka, V. and Síma, P. (1998). Evolutionary Mechanisms of Defense Reactions. Basel, Birkhäuser Verlag. (Library | Amazon | Google Print)

203. Vilmos, P. and Kurucz, E. (1998). "Insect immunity: evolutionary roots of the mammalian innate immune system." Immunology Letters 62(2): 59-66. (PubMed)

204. Armstrong, P. B. and Quigley, J. P. (1999). "Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system." Developmental and Comparative Immunology 23(4-5): 375-390. (PubMed)

205. dos Remedios, N. J., Ramsland, P. A., Hook, J. W. and Raison, R. L. (1999). "Identification of a homologue of CD59 in a cyclostome: implications for the evolutionary development of the complement system." Developmental and Comparative Immunology 23(1): 1-14. (PubMed)

206. Flajnik, M. F., Ohta, Y., Namikawa-Yamada, C. and Nonaka, M. (1999). "Insight into the primordial MHC from studies in ectothermic vertebrates." Immunological Reviews 167: 59-67. (PubMed)

207. Gross, P. S., Al-Sharif, W. Z., Clow, L. A. and Smith, L. C. (1999). "Echinoderm immunity and the evolution of the complement system." Developmental and Comparative Immunology 23(4-5): 429-442. (PubMed)

208. Hoffmann, J. A., Kafatos, F. C., Janeway, C. A. and Ezekowitz, R. A. (1999). "Phylogenetic perspectives in innate immunity." Science 284(5418): 1313-1318. (PubMed)

209. Lewis, S. M. (1999). "Evolution of Immunoglobulin and T-Cell Receptor Gene Assembly." Annals of the New York Academy of Sciences 870: 58-67. (Google Scholar | Journal | PubMed)

210. Litman, G. W., Anderson, M. K. and Rast, J. P. (1999). "Evolution of antigen binding receptors." Annual Review of Immunology 17: 109-147. (Google Scholar | DOI | Journal | PubMed)

211. Magor, B. G., De Tomaso, A., Rinkevich, B. and Weissman, I. L. (1999). "Allorecognition in colonial tunicates: protection against predatory cell lineages?" Immunological Reviews 167: 69-79. (PubMed)

212. Nonaka, M., Azumi, K., Ji, X., Namikawa-Yamada, C., Sasaki, M., Saiga, H., Dodds, A. W., Sekine, H., Homma, M. K., Matsushita, M., Endo, Y. and Fujita, T. (1999). "Opsonic complement component C3 in the solitary ascidian, Halocynthia roretzi." Journal of Immunology 162(1): 387-391. (PubMed)

213. Nonaka, M. and Azumi, K. (1999). "Opsonic complement system of the solitary ascidian, Halocynthia roretzi." Developmental and Comparative Immunology 23(4-5): 421-427. (PubMed)

214. Parham P. (editor) (1999). "Genomic organisation of the MHC: structure, origin and function." Immunological Reviews 167: 1-379. (Google Scholar)

215. Schatz, D. G. (1999). "Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system." Immunologic Research 19(2-3): 169-182. (Google Scholar | PubMed)

216. Schluter, S. F., Bernstein, R. M., Bernstein, H. and Marchalonis, J. J. (1999). "'Big Bang' emergence of the combinatorial immune system." Developmental and Comparative Immunology 23(2): 107-111. (Google Scholar | DOI | Journal | PubMed)

217. Smith, L. C., Azumi, K. and Nonaka, M. (1999). "Complement systems in invertebrates. The ancient alternative and lectin pathways." Immunopharmacology 42(1-3): 107-120. (PubMed)

218. Du Pasquier, L. (2000). "The Phylogenetic Origin of Antigen-Specific Receptors." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 159-185. (Library | PubMed | Amazon | Google Print)

219. Du Pasquier, L. and Litman, G. W., eds. (2000). Origin and Evolution of the Vertebrate Immune System. Current Topics in Microbiology and Immunology. Berlin, Springer. (Library | Publisher | Amazon | Google Print)

220. Flajnik, M. F. and Rumfelt, L. L. (2000). "Early and natural antibodies in non-mammalian vertebrates." Current Topics in Microbiology and Immunology 252: 233-240. (PubMed)

221. Flajnik, M. F. and Rumfelt, L. L. (2000). "The immune system of cartilaginous fish." Current Topics in Microbiology and Immunology 248: 249-270. (PubMed)

222. Grosberg, R. K. and Hart, M. W. (2000). "Mate selection and the evolution of highly polymorphic self/nonself recognition genes." Science 289(5487): 2111-2114. (PubMed)

223. Gross, P. S., Clow, L. A. and Smith, L. C. (2000). "SpC3, the complement homologue from the purple sea urchin, Strongylocentrotus purpuratus, is expressed in two subpopulations of the phagocytic coelomocytes." Immunogenetics 51(12): 1034-1044. (PubMed)

224. Hansen, J. D. and McBlane, J. F. (2000). "Recombination-Activating Genes, Transposition, and the Lymphoid-Specific Combinatorial Immune System: A Common Evolutionary Connection." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 111-135. (Library | PubMed | Amazon | Google Print)

225. Hassanin, A., Golub, R., Lewis, S. M. and Wu, G. E. (2000). "Evolution of the recombination signal sequences in the Ig heavy-chain variable region locus of mammals." Proceedings of the National Academy of Sciences 97(21): 11415-11420. (PubMed)

226. Ishikawa, G., Azumi, K. and Yokosawa, H. (2000). "Involvement of tyrosine kinase and phosphatidylinositol 3-kinase in phagocytosis by ascidian hemocytes." Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 125(3): 351-357. (Journal | PubMed)

227. Laird, D. J., De Tomaso, A. W., Cooper, M. D. and Weissman, I. L. (2000). "50 million years of chordate evolution: seeking the origins of adaptive immunity." Proceedings of the National Academy of Sciences 97(13): 6924-6926. (PubMed)

228. Lee, S. S., Fitch, D., Flajnik, M. F. and Hsu, E. (2000). "Rearrangement of immunoglobulin genes in shark germ cells." Journal of Experimental Medicine 191(10): 1637-1648. (PubMed)

229. Lewis, S. M. and Wu, G. E. (2000). "The old and the restless." Journal of Experimental Medicine 191(10): 1631-1636. (Google Scholar | DOI | Journal | PubMed)

230. Meister, M., Hetru, C. and Hoffmann, J. A. (2000). "The antimicrobial host defense of Drosophila." Current Topics in Microbiology and Immunology 248: 17-36. (PubMed)

231. Nair, S. V., Pearce, S., Green, P. L., Mahajan, D., Newton, R. A. and Raftos, D. A. (2000). "A collectin-like protein from tunicates." Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 125(2): 279-289. (Journal | PubMed)

232. Nonaka, M. and Smith, S. L. (2000). "Complement system of bony and cartilaginous fish." Fish & Shellfish Immunology 10(3): 215-228. (PubMed)

233. Nonaka, M. (2000). "Origin and evolution of the Complement System." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 37-50. (Library | PubMed | Amazon | Google Print)

234. Opal, S. M. (2000). "Phylogenetic and functional relationships between coagulation and the innate immune response." Critical Care Medicine 28(9): S77-S80. (Google Scholar | Journal | PubMed)

235. Richards, M. H. and Nelson, J. L. (2000). "The Evolution of Vertebrate Antigen Receptors: A Phylogenetic Approach." Molecular Biology and Evolution 17(1): 146-155. (Google Scholar | Journal | PubMed)

236. Roth, D. B. (2000). "From lymphocytes to sharks: V(D)J recombinase moves to the germline." Genome Biology 1(2): 1014.1011-1014.1014. (Google Scholar | DOI | Journal | PubMed)

237. Vaandrager, J.-W., Schuuring, E., Philippo, K. and Kluin, P. M. (2000). "V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma." Blood 96(5): 1947-1952. (Google Scholar | Journal | PubMed)

238. De Gregorio, E., Spellman, P. T., Rubin, G. M. and Lemaitre, B. (2001). "Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays." Proceedings of the National Academy of Sciences 98(22): 12590-12595. (PubMed)

239. Du Pasquier, L. (2001). "The immune system of invertebrates and vertebrates." Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 129(1): 1-15. (Google Scholar | DOI | Journal | PubMed)

240. Flajnik, M. F. and Kasahara, M. (2001). "Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system." Immunity 15(3): 351-362. (PubMed)

241. Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R. and Kawabata, S. (2001). "The 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems." Proceedings of the National Academy of Sciences 98(24): 13519-13524. (PubMed)

242. Kimbrell, D. A. and Beutler, B. (2001). "The evolution and genetics of innate immunity." Nature Reviews Genetics 2(4): 256-267. (PubMed)

243. Magor, B. G. and Magor, K. E. (2001). "Evolution of effectors and receptors of innate immunity." Developmental and Comparative Immunology 25(8-9): 651-682. (PubMed)

244. Marchalonis, J. J., Adelman, M. K., Zeitler, B. J., Sarazin, P. M., Jaqua, P. M. and Schluter, S. F. (2001). "Evolutionary factors in the emergence of the combinatorial germline antibody repertoire." Advances in Experimental Medicine and Biology 484: 13-30. (PubMed)

245. Miyazawa, S., Azumi, K. and Nonaka, M. (2001). "Cloning and characterization of integrin alpha subunits from the solitary ascidian, Halocynthia roretzi." Journal of Immunology 166(3): 1710-1715. (PubMed)

246. Mushegian, A. and Medzhitov, R. (2001). "Evolutionary perspective on innate immune recognition." Journal of Cell Biology 155(5): 705-710. (PubMed)

247. Nonaka, M. (2001). "Evolution of the complement system." Current Opinion in Immunology 13(1): 69-73. (PubMed)

248. Nonaka, M. and Miyazawa, S. (2001). "Evolution of the Initiating Enzymes of the Complement System." Genome Biology 3(1): 1001.1001-1001.1005. (Google Scholar | DOI | Journal | PubMed)

249. Ramsland, P. A., Kaushik, A., Marchalonis, J. J. and Edmundson, A. B. (2001). "Incorporation of long CDR3s into V domains: implications for the structural evolution of the antibody-combining site." Experimental and Clinical Immunogenetics 18(4): 176-198. (DOI | Journal | PubMed)

250. Rumfelt, L. L., Avila, D., Diaz, M., Bartl, S., McKinney, E. C. and Flajnik, M. F. (2001). "A shark antibody heavy chain encoded by a nonsomatically rearranged VDJ is preferentially expressed in early development and is convergent with mammalian IgG." Proceedings of the National Academy of Sciences 98(4): 1775-1780. (PubMed)

251. Sahu, A. and Lambris, J. D. (2001). "Structure and biology of complement protein C3, a connecting link between innate and acquired immunity." Immunological Reviews 180: 35-48. (PubMed)

252. Smith, L. C., Clow, L. A. and Terwilliger, D. P. (2001). "The ancestral complement system in sea urchins." Immunological Reviews 180: 16-34. (PubMed)

253. Xu, Y., Narayana, S. V. and Volanakis, J. E. (2001). "Structural biology of the alternative pathway convertase." Immunological Reviews 180: 123-135. (PubMed)

254. Zarkadis, I. K., Mastellos, D. and Lambris, J. D. (2001). "Phylogenetic aspects of the complement system." Developmental and Comparative Immunology 25(8-9): 745-762. (Google Scholar | DOI | Journal | PubMed)

255. Banerjee-Basu, S. and Baxevanis, A. D. (2002). "The DNA-binding region of RAG 1 is not a homeodomain." Genome Biology 3(8): interactions1004.1001-1004.1004. (DOI | Journal | PubMed)

256. Beck, G., Ellis, T. W., Habicht, G. S., Schluter, S. F. and Marchalonis, J. J. (2002). "Evolution of the acute phase response: iron release by echinoderm (Asterias forbesi) coelomocytes, and cloning of an echinoderm ferritin molecule." Developmental and Comparative Immunology 26(1): 11-26. (PubMed)

257. Cannon, J. P., Haire, R. N. and Litman, G. W. (2002). "Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate." Nature Immunology 3(12): 1200-1207. (Google Scholar | DOI | Journal | PubMed)

258. Cohn, M. (2002). "The immune system: a weapon of mass destruction invented by evolution to even the odds during the war of the DNAs." Immunological Reviews 185: 24-38. (PubMed)

259. Du Pasquier, L. (2002). "Several MHC-linked Ig superfamily genes have features of ancestral antigen-specific receptor genes." Current Topics in Microbiology and Immunology 266: 57-71. (PubMed)

260. Flajnik, M. F. (2002). "Comparative analyses of immunoglobulin genes: surprises and portents." Nature Reviews Immunology 2(9): 688-698. (Google Scholar | DOI | Journal | PubMed)

261. Fujita, T. (2002). "Evolution of the lectin-complement pathway and its role in innate immunity." Nature Reviews Immunology 2(5): 346-353. (PubMed)

262. Gellert, M. (2002). "V(D)J recombination: RAG proteins, repair factors, and regulation." Annual Review of Biochemistry 71: 101-132. (PubMed)

263. Greenberg, A. S., Avila, D., Hughes, M., Hughes, A., McKinney, E. C. and Flajnik, M. F. (2002). "A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks." Nature 374(6518): 168-173. (Google Scholar | DOI | Journal | PubMed)

264. Hoffmann, J. A. and Reichhart, J. M. (2002). "Drosophila innate immunity: an evolutionary perspective." Nature Immunology 3(2): 121-126. (PubMed)

265. Kaufman, J. (2002). "The origins of the adaptive immune system: whatever next?" Nature Immunology 3(12): 1124-1125. (Google Scholar | DOI | Journal | PubMed)

266. Krem, M. M. and Di Cera, E. (2002). "Evolution of enzyme cascades from embryonic development to blood coagulation." Trends in Biochemical Sciences 27(2): 67-74. (Google Scholar | DOI | Journal | PubMed)

267. Laird, D. J. (2002). "Immune System." Encyclopedia of Evolution. Edited by M. Pagel. Oxford, Oxford University Press. 2: 558-564. (Library | Publisher | Amazon | Google Print)

268. Langman, R. E. and Cohn, M. (2002). "If the immune repertoire evolved to be large, random, and somatically generated, then." Cellular Immunology 216(1-2): 15-22. (PubMed)

269. Marchalonis, J. J., Jensen, I. and Schluter, S. F. (2002). "Structural, antigenic and evolutionary analyses of immunoglobulins and T cell receptors." Journal of Molecular Recognition 15(5): 260-271. (Google Scholar | DOI | Journal | PubMed)

270. Marchalonis, J. J., Kaveri, S., Lacroix-Desmazes, S. and Kazatchkine, M. D. (2002). "Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system." FASEB Journal 16(8): 842-848. (Google Scholar | Journal | PubMed)

271. Mayer, W. E., Uinuk-Ool, T., Tichy, H., Gartland, L. A., Klein, J. and Cooper, M. D. (2002). "Isolation and characterization of lymphocyte-like cells from a lamprey." Proceedings of the National Academy of Sciences 99(22): 14350-14355. (Google Scholar | DOI | Journal | PubMed)

272. Menezes, H. and Jared, C. (2002). "Immunity in plants and animals: common ends through different means using similar tools." Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 132(1): 1-7. (Journal | PubMed)

273. Neuberger, M. S. (2002). "Novartis Medal Lecture. Antibodies: a paradigm for the evolution of molecular recognition." Biochemical Society Transactions 30(4): 341-350. (Journal | PubMed)

274. Nurnberger, T. and Brunner, F. (2002). "Innate immunity in plants and animals: emerging parallels between the recognition of general elicitors and pathogen-associated molecular patterns." Current Opinion in Plant Biology 5(4): 318-324. (PubMed)

275. Suzuki, M. M., Satoh, N. and Nonaka, M. (2002). "C6-like and C3-like molecules from the cephalochordate, amphioxus, suggest a cytolytic complement system in invertebrates." Journal of Molecular Evolution 54(5): 671-679. (PubMed)

276. Terado, T., Nonaka, M. I., Nonaka, M. and Kimura, H. (2002). "Conservation of the modular structure of complement factor I through vertebrate evolution." Developmental and Comparative Immunology 26(5): 403-413. (PubMed)

277. Uinuk-Ool, T., Mayer, W. E., Sato, A., Dongak, R., Cooper, M. D. and Klein, J. (2002). "Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes." Proceedings of the National Academy of Sciences 99(22): 14356-14361. (Google Scholar | DOI | Journal | PubMed)

278. Altmann, S. M., Mellon, M. T., Distel, D. L. and Kim, C. H. (2003). "Molecular and functional analysis of an interferon gene from the zebrafish, Danio rerio." Journal of Virology 77(3): 1992-2002. (PubMed)

279. Azumi, K., De Santis, R., De Tomaso, A., Rigoutsos, I., Yoshizaki, F., Pinto, M. R., Marino, R., Shida, K., Ikeda, M., Arai, M., Inoue, Y., Shimizu, T., Satoh, N., Rokhsar, D. S., Du Pasquier, L., Kasahara, M., Satake, M. and Nonaka, M. (2003). "Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: "waiting for Godot"." Immunogenetics 55(8): 570-581. (PubMed)

280. Bartl, S., Miracle, A. L., Rumfelt, L. L., Kepler, T. B., Mochon, E., Litman, G. W. and Flajnik, M. F. (2003). "Terminal deoxynucleotidyl transferases from elasmobranchs reveal structural conservation within vertebrates." Immunogenetics 55(9): 594-604. (PubMed)

281. Clatworthy, A. E., Valencia, M. A., Haber, J. E. and Oettinger, M. A. (2003). "V(D)J recombination and RAG-mediated transposition in yeast." Molecular Cell 12(2): 489-499. (Google Scholar | DOI | Journal | PubMed)

282. Flajnik, M. F., Miller, K. and Du Pasquier, L. (2003). "Evolution of the Immune System." Fundamental Immunology. Edited by W. E. Paul. Philadelphia, Lippincott Williams & Wilkins: 519-570. (Library | Amazon | Google Print)

283. Market, E. and Papavasiliou, F. N. (2003). "V(D)J Recombination and the Evolution of the Adaptive Immune System." PLoS Biology 1(1): 24-27. (Google Scholar | DOI | Journal | PubMed)

284. Messier, T. L., O'Neill, J. P., Hou, S.-M., Nicklas, J. A. and Finette, B. A. (2003). "In vivo transposition mediated by V(D)J recombinase in human T lymphocytes." The EMBO Journal 22(6): 1381-1388. (Google Scholar | DOI | Journal | PubMed)

285. Ohinata, Y., Sutou, S. and Mitsui, Y. (2003). "A novel testis-specific RAG2-like protein, Peas: its expression in pachytene spermatocyte cytoplasm and meiotic chromatin." FEBS Letters 537(1-3): 1-5. (PubMed)

286. Ota, T., Rast, J. P., Litman, G. W. and Amemiya, C. T. (2003). "Lineage-restricted retention of a primitive immunoglobulin heavy chain isotype within the Dipnoi reveals an evolutionary paradox." Proceedings of the National Academy of Sciences 100(5): 2501-2506. (PubMed)

287. Rothenberg, E. V. and Davidson, E. H. (2003). "Regulatory Co-options in the Evolution of Deuterostome Immune Systems." Innate Immunity. Edited by R. A. B. Ezekowitz and J. A. Hoffman. Totowa, NJ, Humana Press: 61-87. (Google Print)

288. Schluter, S. F. and Marchalonis, J. J. (2003). "Cloning of shark RAG2 and characterization of the RAG1/RAG2 gene locus." FASEB Journal 17(3): 470-472. (PubMed)

289. Sunyer, J. O., Boshra, H., Lorenzo, G., Parra, D., Freedman, B. and Bosch, N. (2003). "Evolution of complement as an effector system in innate and adaptive immunity." Immunologic Research 27(2-3): 549-564. (PubMed)

290. Adelman, M. K., Schluter, S. F. and Marchalonis, J. J. (2004). "The natural antibody repertoire of sharks and humans recognizes the potential universe of antigens." Protein Journal 23(2): 103-118. (Google Scholar | PubMed)

291. Anderson, M. K., Pant, R., Miracle, A. L., Sun, X., Luer, C. A., Walsh, C. J., Telfer, J. C., Litman, G. W. and Rothenberg, E. V. (2004). "Evolutionary origins of lymphocytes: ensembles of T cell and B cell transcriptional regulators in a cartilaginous fish." Journal of Immunology 172(10): 5851-5860. (PubMed)

292. Cannon, J. P., Haire, R. N., Rast, J. P. and Litman, G. W. (2004). "The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms." Immunological Reviews 200(1): 12-22. (Google Scholar | DOI | Journal | PubMed)

293. Davis, M. M. (2004). "The evolutionary and structural 'logic' of antigen receptor diversity." Seminars in Immunology 16: 239-243. (Google Scholar | DOI | Journal | PubMed)

294. Du Pasquier, L., Zucchetti, I. and De Santis, R. (2004). "Immunoglobulin superfamily receptors in protochordates: before RAG time." Immunological Reviews 198: 233-248. (PubMed)

295. Du Pasquier, L. (2004). "Speculations on the origin of the vertebrate immune system." Immunology Letters 92(1-2): 3-9. (PubMed)

296. Eason, D. D., Cannon, J. P., Haire, R. N., Rast, J. P., Ostrov, D. A. and Litman, G. W. (2004). "Mechanisms of antigen receptor evolution." Seminars in Immunology 16: 215-226. (Google Scholar | DOI | Journal | PubMed)

297. Flajnik, M. F. and Du Pasquier, L. (2004). "Evolution of innate and adaptive immunity: can we draw a line?" Trends in Immunology 25(12): 640-644. (Google Scholar | DOI | Journal | PubMed)

298. Flajnik, M. F. (2004). "Immunology: another manifestation of GOD." Nature 430(6996): 157-158. (Google Scholar | DOI | Journal | PubMed)

299. Fujita, T., Matsushita, M. and Endo, Y. (2004). "The lectin-complement pathway--its role in innate immunity and evolution." Immunological Reviews 198: 185-202. (PubMed)

300. Fujita, T., Endo, Y. and Nonaka, M. (2004). "Primitive complement system--recognition and activation." Molecular Immunology 41(2-3): 103-111. (PubMed)

301. Galaktionov, V. G. (2004). "Evolutionary Development of the Immunoglobulin Family." Biology Bulletin 31(2): 101-111. (Google Scholar | DOI | Journal | PubMed)

302. Girardin, S. E. and Philpott, D. J. (2004). "Mini-review: the role of peptidoglycan recognition in innate immunity." European Journal of Immunology 34(7): 1777-1782. (PubMed)

303. Gould, S. J., Hildreth, J. E. and Booth, A. M. (2004). "The evolution of alloimmunity and the genesis of adaptive immunity." Quarterly Review of Biology 79(4): 359-382. (Google Scholar | DOI | Journal | PubMed)

304. Haynes, M. R. and Wu, G. E. (2004). "Evolution of the variable gene segments and recombination signal sequences of the human T-cell receptor alpha/delta locus." Immunogenetics 56(7): 470-479. (PubMed)

305. Holmes, E. C. (2004). "Adaptation and Immunity." PLoS Biology 2(9): 1269-1269. (Google Scholar | DOI | Journal | PubMed)

306. Jones, J. M. (2004). "The taming of a transposon: V(D)J recombination and the immune system." Immunological Reviews 200(1): 233-248. (Google Scholar | DOI | Journal | PubMed)

307. Kasahara, M., Suzuki, T. and Du Pasquier, L. (2004). "On the origins of the adaptive immune system: novel insights from invertebrates and cold-blooded vertebrates." Trends in Immunology 25(2): 105-111. (PubMed)

308. Khalturin, K., Panzer, Z., Cooper, M. D. and Bosch, T. C. (2004). "Recognition strategies in the innate immune system of ancestral chordates." Molecular Immunology 41(11): 1077-1087. (PubMed)

309. Miyazawa, S. and Nonaka, M. (2004). "Characterization of novel ascidian beta integrins as primitive complement receptor subunits." Immunogenetics 55(12): 836-844. (PubMed)

310. Nonaka, M. and Yoshizaki, F. (2004). "Primitive complement system of invertebrates." Immunological Reviews 198: 203-215. (PubMed)

311. Nonaka, M. and Yoshizaki, F. (2004). "Evolution of the Complement System." Molecular Immunology 40(12): 897-902. (Google Scholar | DOI | Journal | PubMed)

312. Opal, S. M. (2004). "The nexus between systemic inflammation and disordered coagulation in sepsis." Journal of Endotoxin Research 10(2): 125-129. (PubMed)

313. Pancer, Z., Amemiya, C. T., Ehrhardt, G. R. A., Ceitlin, J., Gartland, G. L. and Cooper, M. D. (2004). "Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey." Nature 430(6996): 174-180. (Google Scholar | DOI | Journal | PubMed)

314. Poitrineau, K., Brown, S. P. and Hochberg, M. E. (2004). "The joint evolution of defence and inducibility against natural enemies." Journal of Theoretical Biology 231(3): 389-396. (PubMed)

315. Raftos, D. and Nair, S. (2004). "Tunicate cytokine-like molecules and their involvement in host defense responses." Progress in Molecular and Subcellular Biology 34: 165-182. (PubMed)

316. Rinkevich, B. (2004). "Primitive immune systems: are your ways my ways?" Immunological Reviews 198: 25-35. (PubMed)

317. Rothenberg, E. V. and Pant, R. (2004). "Origins of lymphocyte developmental programs: transcription factor evidence." Seminars in Immunology 16(4): 227-238. (Google Scholar | DOI | Journal | PubMed)

318. Schatz, D. G. (2004). "Antigen receptor genes and the evolution of a recombinase." Seminars in Immunology 16(4): 245-256. (Google Scholar | DOI | Journal | PubMed)

319. Stavnezer, J. and Amemiya, C. T. (2004). "Evolution of isotype switching." Seminars in Immunology 16(4): 257-275. (Google Scholar | DOI | Journal | PubMed)

320. Suzuki, T., Shin, I. T., Kohara, Y. and Kasahara, M. (2004). "Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes." Developmental and Comparative Immunology 28(10): 993-1003. (PubMed)

321. van den Berg, T. K., Yoder, J. A. and Litman, G. W. (2004). "On the origins of adaptive immunity: innate immune receptors join the tale." Trends in Immunology 25(1): 11-16. (PubMed)

322. Xiao, Y., Hughes, A. L., Ando, J., Matsuda, Y., Cheng, J. F., Skinner-Noble, D. and Zhang, G. (2004). "A genome-wide screen identifies a single beta-defensin gene cluster in the chicken: implications for the origin and evolution of mammalian defensins." BMC Genomics 5(1): 56. (PubMed)

323. Zhou, L., Mitra, R., Atkinson, P. W., Hickman, A. B., Dyda, F. and Craig, N. L. (2004). "Transposition of hAT elements links transposable elements and V(D)J recombination." Nature 432: 995-1001. (Google Scholar | DOI | Journal | PubMed)

324. Alder, M. N., Rogozin, I. B., Iyer, L. M., Glazko, G. V., Cooper, M. D. and Pancer, Z. (2005). "Diversity and function of adaptive immune receptors in a jawless vertebrate." Science 310(5756): 1970-1973. (PubMed)

325. Cannon, J. P., Haire, R. N., Pancer, Z., Mueller, M. G., Skapura, D., Cooper, M. D. and Litman, G. W. (2005). "Variable Domains and a VpreB-like molecule are present in a jawless vertebrate." Immunogenetics 56(12): 924-929. (Google Scholar | DOI | Journal | PubMed)

326. Cohn, M. (2005). "The common sense of the self-nonself discrimination." Springer Seminars in Immunopathology 27(1): 3-17. (PubMed)

327. Czompoly, T., Olasz, K., Simon, D., Nyarady, Z., Palinkas, L., Czirjak, L., Berki, T. and Nemeth, P. (2005). "A possible new bridge between innate and adaptive immunity: Are the anti-mitochondrial citrate synthase autoantibodies components of the natural antibody network?" Molecular Immunology. (PubMed)

328. De Tomaso, A. W., Nyholm, S. V., Palmeri, K. J., Ishizuka, K. J., Ludington, W. B., Mitchel, K. and Weissman, I. L. (2005). "Isolation and characterization of a protochordate histocompatibility locus." Nature 438(7067): 454-459. (DOI | Journal | PubMed)

329. Du Pasquier, L. (2005). "Germline and somatic diversification of immune recognition elements in Metazoa." Immunology Letters. (PubMed)

330. Du Pasquier, L. (2005). "Meeting the demand for innate and adaptive immunities during evolution." Scandinavian Journal of Immunology 62(s1): 39-48. (Google Scholar | DOI | Journal | PubMed)

331. Dunne, D. W. and Cooke, A. (2005). "A worm's eye view of the immune system: consequences for evolution of human autoimmune disease." Nature Reviews Immunology 5(5): 420-426. (PubMed)

332. Janssen, B. J. C., Huizinga1, E. G., Raaijmakers, H. C. A., Roos, A., Daha, M. R., Nilsson-Ekdahl, K., Nilsson, B. and Gros, P. (2005). "Structures of complement component C3 provide insights into the function and evolution of immunity." Nature 437(7058): 505-511. (Google Scholar | DOI | Journal | PubMed)

333. Kapitonov, V. V. and Jurka, J. (2005). "RAG1 Core and V(D)J Recombination Signal Sequences Were Derived from Transib Transposons." PLoS Biology 3(6): e181:0001-0014. (Google Scholar | DOI | Journal | PubMed)

334.* Klein, J. and Nikolaidis, N. (2005). "The descent of the antibody-based immune system by gradual evolution." Proceedings of the National Academy of Sciences 102(1): 169-174. (Google Scholar | DOI | Journal | PubMed)

335. Liddington, R. and Bankston, L. (2005). "Structural biology: origins of chemical biodefence." Nature 437(7058): 484-485. (PubMed)

336. Litman, G. W., Cannon, J. P. and Dishaw, L. J. (2005). "Reconstructing immune phylogeny: new perspectives." Nature Reviews Immunology 5(11): 866-879. (PubMed)

337. Litman, G. W., Cannon, J. P. and Rast, J. P. (2005). "New insights into alternative mechanisms of immune receptor diversification." Advances in Immunology 87: 209-236. (PubMed)

338. Litman, G. W. (2005). "Histocompatibility: colonial match and mismatch." Nature 438(7067): 437-439. (DOI | Journal | PubMed)

339. Martinelli, C. and Reichhart, J. M. (2005). "Evolution and integration of innate immune systems from fruit flies to man: lessons and questions." Journal of Endotoxin Research 11(4): 243-248. (PubMed)

340. Pancer, Z., Saha, N. R., Kasamatsu, J., Suzuki, T., Amemiya, C. T., Kasahara, M. and Cooper, M. D. (2005). "Variable lymphocyte receptors in hagfish." Proceedings of the National Academy of Sciences 102(26): 9224-9229. (PubMed)

341. Plouffe, D. A., Hanington, P. C., Walsh, J. G., Wilson, E. C. and Belosevic, M. (2005). "Comparison of select innate immune mechanisms of fish and mammals." Xenotransplantation 12(4): 266-277. (PubMed)

342. Prugnolle, F., Manica, A., Charpentier, M., Guegan, J. F., Guernier, V. and Balloux, F. (2005). "Pathogen-driven selection and worldwide HLA class I diversity." Current Biology 15(11): 1022-1027. (PubMed)

343. Schatz, D. G. and Spanopoulou, E. (2005). "Biochemistry of V(D)J recombination." Current Topics in Microbiology and Immunology 290: 49-85. (Google Scholar | Journal | PubMed)

344. Sunyer, J. O., Boshra, H. and Li, J. (2005). "Evolution of anaphylatoxins, their diversity and novel roles in innate immunity: insights from the study of fish complement." Veternary Immunology and Immunopathology 108(1-2): 77-89. (PubMed)

345. Suzuki, T., Shin, I. T., Fujiyama, A., Kohara, Y. and Kasahara, M. (2005). "Hagfish leukocytes express a paired receptor family with a variable domain resembling those of antigen receptors." Journal of Immunology 174(5): 2885-2891. (PubMed)

346. Yoshizaki, F. Y., Ikawa, S., Satake, M., Satoh, N. and Nonaka, M. (2005). "Structure and the evolutionary implication of the triplicated complement factor B genes of a urochordate ascidian, Ciona intestinalis." Immunogenetics 56(12): 930-942. (PubMed)

347. Belov, K., Deakin, J. E., Papenfuss, A. T., Baker, M. L., Melman, S. D., Siddle, H. V., Gouin, N., Goode, D. L., Sargeant, T. J., Robinson, M. D., Wakefield, M. J., Mahony, S., Cross, J. G., Benos, P. V., Samollow, P. B., Speed, T. P., Graves, J. A. and Miller, R. D. (2006). "Reconstructing an Ancestral Mammalian Immune Supercomplex from a Marsupial Major Histocompatibility Complex." PLoS Biology 4(3): e46. (PubMed)

348. Boehm, T. (2006). "Co-evolution of a primordial peptide-presentation system and cellular immunity." Nature Reviews Immunology 6(1): 79-84. (DOI | Journal | PubMed)

349. Cohn, M. (2006). "What are the commonalities governing the behavior of humoral immune recognitive repertoires?" Developmental and Comparative Immunology 30(1-2): 19-42. (Google Scholar | DOI | Journal | PubMed)

350. Cooper, M. D. and Alder, M. N. (2006). "The Evolution of Adaptive Immune Systems." Cell 124(4): 815-822. (Google Scholar | DOI | Journal | PubMed)

351. Danilova, N. (2006). "The evolution of immune mechanisms." Journal of Experimental Zoology, Part B: Molecular and Developmental Evolution. (Google Scholar | DOI | Journal | PubMed)

352. Fugmann, S. D., Messier, C., Novack, L. A., Cameron, R. A. and Rast, J. P. (2006). "An ancient evolutionary origin of the Rag1/2 gene locus." Proceedings of the National Academy of Sciences 103(10): 3728-3733. (DOI | Journal | PubMed)

353. Joly, E. (2006). "Various hypotheses on MHC evolution suggested by the concerted evolution of CD94L and MHC class Ia molecules." Biology Direct 1(1): 3. (Google Scholar | DOI | Journal | PubMed)

354. Joly, E. and Rouillon, V. (2006). "The orthology of HLA-E and H2-Qa1 is hidden by their concerted evolution with other MHC class I molecules." Biology Direct 1(1): 2. (Google Scholar | DOI | Journal | PubMed)

355. Marchalonis, J. J., Adelman, M. K., Schluter, S. F. and Ramsland, P. A. (2006). "The antibody repertoire in evolution: Chance, selection, and continuity." Developmental and Comparative Immunology 30(1-2): 223-247. (Google Scholar | DOI | Journal | PubMed)

356. Pancer, Z. and Cooper, M. D. (2006). "The Evolution of Adaptive Immunity." Annual Review of Immunology 24. (DOI | Journal | PubMed)

357. Wagner, C. and Hansch, G. M. (2006). "Receptors for complement C3 on T-lymphocytes: relics of evolution or functional molecules?" Molecular Immunology 43(1-2): 22-30. (DOI | Journal | PubMed)

Acknowledgements

Thanks to Andrea Bottaro, Matt Inlay, and the Panda's Thumb crew for suggestions and corrections. Any mistakes that remain are my own.

Immunology in the Spotlight at the Dover 'Intelligent Design' Trial

The May 2006 issue of Nature Immunology contains a "Commentary" essay on the role that evolutionary immunology played in the now-famous cross-examination of Michael Behe on Day 12 of the Kitzmiller v. Dover trial in the fall of 2005. The essay is coauthored by Nick Matzke, NCSE Public Information Project Director and a key behind-the-scenes player in the Kitzmiller case. Matzke teamed up with two immunologists to write the article: Andrea Bottaro (Department of Medicine, Department of Microbiology and Immunology and the James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry) and Matt Inlay (Department of Pathology, Beckman Center, Stanford University). Both are contributors to the Panda's Thumb weblog, and have written detailed critiques of Behe's claims about immunology (Bottaro, Inlay). These critiques served as an inspiration and guide for Matzke during preparation of the immune system section of the Behe cross-examination.

The Nature Immunology commentary reviews the background of the case, the science supporting the transposon model for the evolutionary origin of the adaptive immune system's rearranging antibodies, the problems with Behe's claims about the system, and recounts this dramatic episode of the Behe cross-examination.

Immunology in the spotlight at the Dover 'Intelligent Design' trial

Andrea Bottaro1, Matt A Inlay2 & Nicholas J Matzke3

1 Andrea Bottaro is with the Department of Medicine, Department of Microbiology and Immunology and the James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.

2 Matt A. Inlay is in the Department of Pathology, Beckman Center, Stanford University, Stanford, California 94305, USA.

3 Nicholas J. Matzke is with the National Center for Science Education, Oakland, California 94609, USA.

Correspondence should be addressed to Andrea Bottaro andrea_bottaro@urmc.rochester.edu

Immunology had an unexpected and decisive part in challenging the claims of 'Intelligent Design' proponents at the US trial on the teaching of evolution in public schools in Dover, Pennsylvania.

Evolutionary immunology literature presented at the Dover trial. "We can look high or we can look low, in books or in journals, but the result is the same. The scientific literature has no answers to the question of the origin of the immune system."2

The latest skirmish in the ongoing controversy about the teaching of evolution in US schools ended decisively on 20 December 2005, when the introduction of 'Intelligent Design' (ID) in a public school biology class was struck down by US Federal Judge John E. Jones as an unconstitutional establishment of religion. The case, 'Kitzmiller et al. v. Dover Area School District', was brought by 11 parents from Dover, Pennsylvania, represented pro bono by the Philadelphia law firm Pepper-Hamilton, together with the American Civil Liberties Union and Americans United for the Separation of Church and State and assisted with scientific support by the National Center for Science Education, the Oakland, California–based nonprofit organization devoted to combating creationism. The parents challenged the school district's requirement that administrators read to ninth graders a disclaimer raising doubts about evolution, suggesting ID as a better alternative explanation for life's diversity and referring students to the ID supplemental textbook Of Pandas and People, 60 copies of which had been donated to the school library.

Although the magnitude of the win for science education was a surprise to some, the actual outcome of the trial was in very little doubt, for many reasons. Board members had made clear, through public declarations at board meetings and to the media, their intention to have some form of religious creationism taught in biology classes alongside evolution, which they considered akin to atheism. US Supreme Court rulings have established and repeatedly reaffirmed that governmental policies with the purpose or effect of establishing religion are inadmissible because they violate the First Amendment of the US Constitution. It also did not help their cause that Judge Jones found that some of the board members "either testified inconsistently, or lied outright under oath" about some statements and about the source of the donated Of Pandas and People books, the money for which was raised by one of the board members at his own church.


The most important and far-reaching aspect of the decision, however, was that the judge went beyond the narrow issue of the school board's actions and ruled broadly on the nature of ID and its scientific claims. After a 6-week trial that included extensive expert testimony from both sides on science, philosophy and the history of creationism, Jones ruled that ID is not science but "creationism re-labeled." Coming from the George W. Bush–appointed, lifelong Republican and church-going Judge Jones, the ruling was all the more stinging for ID advocates and made the predictable charge of 'judicial activism' harder to sustain. The ruling is likely to have a substantial effect on many other ongoing cases (and possibly future court decisions) regarding ID and evolution in science curricula from Georgia to Kansas to Ohio.


More fundamentally, the decision represents a considerable setback for ID advocates, who claim that some examples of biological complexity could only have originated by intelligent mechanisms, and for their movement's now almost-20-year-old effort to gain a foothold in school curricula and project an aura of scientific respectability. The ruling is also of great interest to scientists, not only because of its importance for science education but also because much of the trial's extensive expert testimony, both for and opposed to ID, focused directly on weighty scientific topics. Judge Jones analyzed and dismissed the core 'scientific' assertions of the ID movement—immunology had an unexpectedly large and relevant part in his reaching those conclusions.


Although the field of evolutionary and comparative immunology has a long and rich history, dating back at least to 1891 (ref. 1), and remains an exciting and rapidly progressing area of research, its direct involvement in the controversies about evolution in schools can be attributed mainly to Michael Behe, professor of biochemistry at Lehigh University (Bethlehem, Pennsylvania), leading ID advocate and star expert witness for the defense at this trial. In his 1996 book Darwin's Black Box2, a commonly cited example of ID-based 'science', Behe devotes an entire chapter to the immune system, pointing to several of its features as being particularly refractory to evolutionary explanations. Behe's antievolutionary argument relies on a characteristic he calls "irreducible complexity": the requirement for the presence of multiple components of certain complex systems (such as a multiprotein complex or biochemical cascade) for the system to accomplish its function. As such irreducibly complex systems by definition work only when all components are present; Behe claims they cannot arise by the sequential addition and modification of individual elements from simpler pre-existing systems, thus defying 'darwinian' evolutionary explanations.


By analogy with human 'machines', ID advocates argue that irreducibly complex systems are most likely the product of an intelligent, teleological activity. Several scientists, including ourselves, have criticized Behe's argument, pointing out how irreducibly complex systems can arise through known evolutionary mechanisms, such as exaptation, 'scaffolding' and so on. Nevertheless, with few exceptions3, 4, 5, 6, the topic has been explicitly addressed mostly in book reviews7, 8, 9, 10, philosophy journals11, 12 and on the internet, rather than in peer-reviewed scientific publications, which may have allowed it to mostly escape the critical scrutiny of scientists while gaining considerable popularity with the lay public and, in particular, with creationists.


In chapter 6 of Darwin's Black Box, Behe claims that the vertebrate adaptive immune system fulfills the definition of irreducible complexity and hence cannot have evolved. Some of his arguments will seem rather naive and misguided to immunologists. For example, Behe argues that working antibodies must exist in both soluble and membrane form, which therefore must have appeared simultaneously because one form would be useless without the other. He also claims that antibodies are completely functionless without secondary effector mechanisms (such as the complement system), which in turn require antibodies for activation. These putative 'chicken-and-egg' conundrums are easily belied by existing evidence (http://www.talkdesign.org/faqs/Evolving_Immunity.html).


Behe also spends considerable time on what he alleges is a hopelessly intractable problem in evolutionary immunology: the origin of the mechanism of somatic recombination of antigen receptor genes. He argues that because variable-diversity-joining recombination is dependent on the coexistence of proteins encoded by recombination-activating genes (RAG proteins), recombination signal sequences and antigen receptor gene segments, it is ultimately too complex to have arisen by naturalistic, undirected evolutionary means because the three components could not have come together in a 'fell swoop' and would have been useless individually. In fact, Behe confidently declares that the complexity of the immune system "dooms all Darwinian explanations to frustration"2. About the scientific literature, Behe claims it has "no answers" as to how the adaptive immune system may have originated2.


In particular, Behe criticizes a 1994 Proceedings of the National Academy of Science paper advancing the hypothesis that the RAG system evolved by lateral transfer of a prokaryotic transposon13, an idea initially suggested in a 1979 paper14 and expanded in 1992 (ref. 15). Behe ridicules the idea as a "jump in the box of Calvin and Hobbes,"2 with reference to the comic strip in which a child and his stuffed tiger imaginary friend use a large cardboard box for fantasy trips and amazing physical transformations.


The timing for the criticism could not have been worse, as soon after publication of Darwin's Black Box, solid evidence for the transposon hypothesis began accumulating with the demonstration of similarities between the variable-diversity-joining recombination and transposition mechanisms16 and also between shark RAG1 and certain bacterial integrases17. Since then, a steady stream of findings has continued to add more substance to the model, as RAG proteins have been shown to be capable of catalyzing transposition reactions, first in vitro18, 19 and then in vivo20, 21, 22, and to have even closer structural and mechanistic similarities with specific transposases23. Finally, in 2005, the original key prediction of the transposon hypothesis was fulfilled with the identification of a large invertebrate transposon family bearing both recombination signal sequence–like integration sequences and a RAG1 homolog24. When faced with that evidence during an exchange on the internet, Behe simply 'shrugged' and said that evidence was not sufficient, asking instead for an infinitely detailed, step-by-step mutation account (including population sizes, relevant selective pressures and so on) for the events leading to the appearance of the adaptive immune system (http://www.pandasthumb.org/archives/2005/06/behes_meaningle.html).


That background set the stage for the crucial face-off at the trial. Kenneth Miller of Brown University, a cell biologist and textbook author who has written extensively on evolution and creationism, was the lead witness for the plaintiffs. Over the course of his testimony, Miller did his best to explain to the nonscientist audience the mechanisms of antibody gene rearrangement and the evidence corroborating the transposon hypothesis. Then, 10 days later, Behe took the stand. During cross-examination by the plaintiffs' lead counsel Eric Rothschild, Behe reiterated his claim about the scientific literature on the evolution of the immune system, testifying that "the scientific literature has no detailed testable answers on how the immune system could have arisen by random mutation and natural selection." Rothschild then presented Behe with a thick file of publications on immune system evolution, dating from 1971 to 2006, plus several books and textbook chapters. Asked for his response, Behe admitted he had not read many of the publications presented (a small fraction of all the literature on evolutionary immunology of the past 35 years), but summarily rejected them as unsatisfactory and dismissed the idea of doing research on the topic as "unfruitful."


This exchange clearly made an impression on Judge Jones, who specifically described it in his opinion:


In fact, on cross-examination, Professor Behe was questioned concerning his 1996 claim that science would never find an evolutionary explanation for the immune system. He was presented with fifty-eight peer-reviewed publications, nine books, and several immunology textbook chapters about the evolution of the immune system; however, he simply insisted that this was still not sufficient evidence of evolution, and that it was not 'good enough.'


We find that such evidence demonstrates that the ID argument is dependent upon setting a scientifically unreasonable burden of proof for the theory of evolution.


Other important scientific points stood out during trial relating to other purported irreducibly complex systems such as the flagellum and the clotting cascade, the nature of science itself and the lack of experimental tests and supporting peer-reviewed publications for ID. But the stark contrast between the lively and productive field of evolutionary immunology and the stubborn refusal by ID advocates such as Behe to even consider the evidence was undoubtedly crucial in convincing the judge that the ID movement has little to do with science. As Rothschild remarked in his closing argument,


Thankfully, there are scientists who do search for answers to the question of the origin of the immune system. It's the immune system. It's our defense against debilitating and fatal diseases. The scientists who wrote those books and articles toil in obscurity, without book royalties or speaking engagements. Their efforts help us combat and cure serious medical conditions. By contrast, Professor Behe and the entire intelligent design movement are doing nothing to advance scientific or medical knowledge and are telling future generations of scientists, don't bother.


Evolutionary immunologists should be pleasantly surprised by and proud of the effect their scientific accomplishments have had in this landmark judicial case. This commentary is meant to acknowledge their contribution on behalf of the Dover families, their lawyers and all the activists for rigorous science education who have participated in these proceedings. Most importantly, however, the Dover case shows that no scientific field is too remote from the hotly debated topics of the day and that no community is too small and removed from the great urban and scientific centers to be relevant. Immunologists must engage their communities and society at large in events related to public perceptions about science. Now more than ever, the participation of scientists is essential for the crafting of rational policies on scientific research and science education.



REFERENCES
  1. Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation; Delivered at the Pasteur Institute in 1891 (Dover, New York, 1968).
  2. Behe, M.J. Darwin's Black Box: the Biochemical Challenge to Evolution (Free Press, New York, 1996).
  3. Thornhill, R.H. & Ussery, D.W. J. Theor. Biol. 203, 111–116 (2000). | Article | PubMed | ISI | ChemPort |
  4. Aird, W.C. J. Thromb. Haemost. 1, 227–230 (2003). | Article | PubMed | ISI | ChemPort |
  5. Pennock, R.T. Annu. Rev. Genomics Hum. Genet. 4, 143–163 (2003). | Article | PubMed | ISI | ChemPort |
  6. Keller, E.F. Ann. NY Acad. Sci. 981, 189–201 (2002). | PubMed |
  7. Orr, H.A. Boston Review XXI, 28–31 (1996).
  8. Coyne, J.A. Nature 383, 227–228 (1996). | Article | ISI | ChemPort |
  9. Cavalier-Smith, T. Trends Ecol. Evol. 12, 162–163 (1997). | Article |
  10. Pomiankowski, A. New Scientist 151, 44–45 (1996).
  11. Shanks, N. & Joplin, K.H. Philos. Sci. 66, 268–282 (1999). | Article | ISI |
  12. Weber, B. Biol. Philos. 14, 593–605 (1999). | Article | ISI |
  13. Bartl, S. , Baltimore, D. & Weissman, I. Proc. Natl. Acad. Sci. USA 91, 10769–10770 (1994). | PubMed | ChemPort |
  14. Sakano, H. , Huppi, K. , Heinrich, G. & Tonegawa, S. Nature 280, 288–294 (1979). | Article | PubMed | ISI | ChemPort |
  15. Dreyfus, D.H. Mol. Immunol. 29, 807–810 (1992). | Article | PubMed | ISI | ChemPort |
  16. Van Gent, D.C. , Mizuuchi, K. & Gellert, M. Science 271, 1592–1594 (1996). | PubMed | ChemPort |
  17. Bernstein, R.M. , Schulter, S.F. , Bernstein, H. & Marchalonis, J.J. Proc. Natl. Acad. Sci. USA 93, 9454–9459 (1996). | Article | PubMed | ChemPort |
  18. Agrawal, A. , Eastman, Q.M. & Schatz, D.G. Nature 394, 744–751 (1998). | Article | PubMed | ISI | ChemPort |
  19. Hiom, K. , Melek, M. & Gellert, M. Cell 94, 463–470 (1998). | Article | PubMed | ISI | ChemPort |
  20. Vaandrager, J.W. , Schuuring, E. , Philippo, K. & Kluin, P.M. Blood 96, 1947–1952 (2000). | PubMed | ISI | ChemPort |
  21. Clatworthy, A.E. , Valencia, M.A. , Haber, J.E. & Oettinger, M.A. Mol. Cell 12, 489–499 (2003). | Article | PubMed | ISI | ChemPort |
  22. Messier, T.L. , O'Neill, J.P. , Hou, S.M. , Nicklas, J.A. & Finette, B.A. EMBO J. 22, 1381–1388 (2003). | Article | PubMed | ISI | ChemPort |
  23. Zhou, L. et al. Nature 432, 995–1001 (2004). | Article | PubMed | ISI | ChemPort |
  24. Kapitonov, V.V. & Jurka, J. PLoS Biol. 3, e181 (2005). | Article | PubMed | ChemPort |
Acknowledgments
We thank the authors of the articles and books on the evolution of the immune system presented during the trial (http://www.ncseprojects.org/creationism/legal/immune-system-kitzmiller-case) and contributors to Panda's Thumb (http://www.pandasthumb.org) and Talkorigins Archive (http://www.talkorigins.org) for suggestions during the trial and for comments on this manuscript. The decision, trial transcripts and all court documents are available through the National Center for Science Education ( http://www.ncseprojects.org/creationism/legal/intelligent-design-trial-kitzmiller-v-dover).

Scientific literature on the evolutionary origin of the immune system

Supplementary Material

Supplementary Material for: Bottaro, Andrea, Inlay, Matt A., and Matzke, Nicholas J. (2006). "Immunology in the spotlight at the Dover 'Intelligent Design' trial." Nature Immunology. 7(5), 433-435. May 2005. (Subscription no longer required: DOI | Journal | Google Scholar | PubMed | Supplementary Material)

Scientific literature on the evolutionary origin of the immune system

This is the list of books, textbook chapters, and articles that were presented to Defense expert Michael Behe during cross-examination in the Kitzmiller v. Dover Area School District trial about the constitutionality of teaching "intelligent design." The cross-examination was conducted by Pepper-Hamilton attorney Eric Rothschild. Behe summarily dismissed the mass of scientific literature on the evolution of the immune system, despite the fact that it contradicted his previous assertion that the scientific community had "no answers" on the question. This episode was cited in Judge Jones's ruling against intelligent design, and various press accounts.

Sections: BooksTextbook chaptersArticlesNote
See also: Annotated Bibliography | Long Unannotated Bibliography

Books

Beck, G., Cooper, E. L., Habicht, G. S. and Marchalonis, J. J., eds. (1994). Primordial Immunity: Foundations for the Vertebrate Immune System. New York, The New York Academy of Sciences. (Library | PubMed | Amazon | Google Print)

Du Pasquier, L. and Litman, G. W., eds. (2000). Origin and Evolution of the Vertebrate Immune System. Current Topics in Microbiology and Immunology. Berlin, Springer. (Library | Amazon | Google Print)

Hoffman, J. A., Janeway, C. A. and Natori, S., eds. (1994). Phylogenetic Perspectives in Immunity: The Insect Host Defense. Austin, R. G. Landes Company. (Library | Amazon | Google Print)

Kelsoe, G. and Schulze, D. H., eds. (1987). Evolution and Vertebrate Immunity: The Antigen-Receptor and MHC Gene Families. Austin, University of Texas Press. (Library | Amazon | Google Print)

Manning, M. J., ed. (1980). Phylogeny of Immunological Memory. Developments in Immunology. Amsterdam, Elsevier/North-Holland Biomedical Press. (Library | Amazon | Google Print)

Marchalonis, J. J. (1976). Immunity in Evolution. Cambridge, Mass., Harvard University Press. (Library | Amazon | Google Print)

Síma, P. and Vetvicka, V. (1990). Evolution of Immune Reactions. Boca Raton, CRC Press. (Library | Amazon | Google Print)

Stewart, J. (1994). The Primordial VRM System and the Evolution of Vertebrate Immunity. Austin, R. G. Landes. (Library | Amazon | Google Print)

Vetvicka, V. and Síma, P. (1998). Evolutionary Mechanisms of Defense Reactions. Basel, Birkhäuser Verlag. (Library | Amazon | Google Print)

Vetvicka, V., Síma, P., Cooper, E. L., Bilej, M. and Roch, P. (1994). Immunology of Annelids. Boca Raton, CRC Press. (Library | Amazon | Google Print)

Warr, G. W. and Cohen, N., eds. (1991). Phylogenesis of Immune Functions. Boca Raton, CRC Press. (Library | Amazon | Google Print)



Textbook chapters

Flajnik, M. F., Miller, K. and Du Pasquier, L. (2003). "Evolution of the Immune System." Fundamental Immunology. Edited by W. E. Paul. Philadelphia, Lippincott Williams & Wilkins: 519-570. (Library | Amazon | Google Print)

Klein, J. (1986). "Evolution of Mhc." Natural History of the Major Histocompatibility Complex. New York, John Wiley & Sons: 715-762. (Library | Google Print)

Síma, P. and Vetvicka, V. (1992). "Evolution of Immune Accessory Functions." Immune System Accessory Cells. Edited by L. Fornusek and P. Síma. Boca Raton, CRC Press: 1-55. (Library | Amazon | Google Print)



Articles

Agrawal, A., Eastman, Q. M. and Schatz, D. G. (1998). "Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system." Nature 394(6695): 744-751. (PubMed | DOI | Journal | Google Scholar)

Bartl, S., Baltimore, D. and Weissman, I. L. (1994). "Molecular evolution of the vertebrate immune system." Proceedings of the National Academy of Sciences 91(23): 10769-10770. (PubMed | Journal | JSTOR | Google Scholar)

Bernstein, R. M., Schluter, S. F., Bernstein, H. and Marchalonis, J. J. (1996). "Primordial emergence of the recombination activating gene 1 (RAG1): Sequence of the complete shark gene indicates homology to microbial integrases." Proceedings of the National Academy of Sciences 93(18): 9454-9459. (PubMed | Journal | JSTOR | Google Scholar)

Burnet, F. M. (1971). "Self-recognition in colonial marine forms and flowering plants in relation to the evolution of immunity." Nature 232(5308): 230. (PubMed | DOI | Journal | Google Scholar)

Cannon, J. P., Haire, R. N. and Litman, G. W. (2002). "Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate." Nature Immunology 3(12): 1200-1207. (PubMed | DOI | Journal | Google Scholar)

Cannon, J. P., Haire, R. N., Pancer, Z., Mueller, M. G., Skapura, D., Cooper, M. D. and Litman, G. W. (2005). "Variable Domains and a VpreB-like molecule are present in a jawless vertebrate." Immunogenetics 56(12): 924-929. (PubMed | DOI | Journal | Google Scholar)

Cannon, J. P., Haire, R. N., Rast, J. P. and Litman, G. W. (2004). "The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms." Immunological Reviews 200(1): 12-22. (PubMed | DOI | Journal | Google Scholar)

Clatworthy, A. E., Valencia, M. A., Haber, J. E. and Oettinger, M. A. (2003). "V(D)J recombination and RAG-mediated transposition in yeast." Molecular Cell 12(2): 489-499. (PubMed | DOI | Journal | Google Scholar)

Cohn, M. (2006). "What are the commonalities governing the behavior of humoral immune recognitive repertoires?" Developmental and Comparative Immunology 30(1-2): 19-42. (PubMed | DOI | Journal | Google Scholar)

Davis, M. M. (2004). "The evolutionary and structural 'logic' of antigen receptor diversity." Seminars in Immunology 16: 239-243. (PubMed | DOI | Journal | Google Scholar)

Dreyfus, D. H. (1992). "Evidence suggesting an evolutionary relationship between transposable elements and immune system recombination sequences." Molecular Immunology 29(6): 807-810. (PubMed | DOI | Journal | Google Scholar)

Du Pasquier, L. (2000). "The Phylogenetic Origin of Antigen-Specific Receptors." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 159-185. (Library | PubMed | Amazon | Google Print)

Du Pasquier, L. (2001). "The immune system of invertebrates and vertebrates." Comparative Biochemistry and Physiology Part B Biochemistry & Molecular Biology 129(1): 1-15. (PubMed | DOI | Journal | Google Scholar)

Du Pasquier, L. (2005). "Meeting the demand for innate and adaptive immunities during evolution." Scandinavian Journal of Immunology 62(s1): 39-48. (PubMed | DOI | Journal | Google Scholar)

Eason, D. D., Cannon, J. P., Haire, R. N., Rast, J. P., Ostrov, D. A. and Litman, G. W. (2004). "Mechanisms of antigen receptor evolution." Seminars in Immunology 16: 215-226. (PubMed | DOI | Journal | Google Scholar)

Flajnik, M. F. and Du Pasquier, L. (2004). "Evolution of innate and adaptive immunity: can we draw a line?" Trends in Immunology 25(12): 640-644. (PubMed | DOI | Journal | Google Scholar)

Galaktionov, V. G. (2004). "Evolutionary Development of the Immunoglobulin Family." Biology Bulletin 31(2): 101-111. (PubMed | DOI | Journal | Google Scholar)

Gould, S. J., Hildreth, J. E. and Booth, A. M. (2004). "The evolution of alloimmunity and the genesis of adaptive immunity." Quarterly Review of Biology 79(4): 359-382. (PubMed | DOI | Journal | Google Scholar)

Hansen, J. D. and McBlane, J. F. (2000). "Recombination-Activating Genes, Transposition, and the Lymphoid-Specific Combinatorial Immune System: A Common Evolutionary Connection." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 111-135. (Library | PubMed | Amazon | Google Print)

Holmes, E. C. (2004). "Adaptation and Immunity." PLoS Biology 2(9): 1269-1269. (PubMed | DOI | Journal | Google Scholar)

Hughes, A. L. and Yeager, M. (1997). "Molecular evolution of the vertebrate immune system." BioEssays 19(9): 777-786. (PubMed | Google Scholar)

Janssen, B. J. C., Huizinga, E. G., Raaijmakers, H. C. A., Roos, A., Daha, M. R., Nilsson-Ekdahl, K., Nilsson, B. and Gros, P. (2005). "Structures of complement component C3 provide insights into the function and evolution of immunity." Nature 437(7058): 505-511. (PubMed | DOI | Journal | Google Scholar)

Ji, X., Azumi, K., Sasaki, M. and Nonaka, M. (1997). "Ancient origin of the complement lectin pathway revealed by molecular cloning of mannan binding protein-associated serine protease from a urochordate, the Japanese ascidian, Halocynthia roretzi." Proceedings of the National Academy of Sciences 94(12): 6340-6345. (PubMed | Journal | Google Scholar)

Jones, J. M. (2004). "The taming of a transposon: V(D)J recombination and the immune system." Immunological Reviews 200(1): 233-248. (PubMed | DOI | Journal | Google Scholar)

Kapitonov, V. V. and Jurka, J. (2005). "RAG1 Core and V(D)J Recombination Signal Sequences Were Derived from Transib Transposons." Public Library of Science Biology 3(6): e181:0001-0014. (PubMed | DOI | Journal | Google Scholar)

Kaufman, J. (2002). "The origins of the adaptive immune system: whatever next?" Nature Immunology 3(12): 1124-1125. (PubMed | DOI | Journal | Google Scholar)

Klein, J. and Nikolaidis, N. (2005). "The descent of the antibody-based immune system by gradual evolution." Proceedings of the National Academy of Sciences 102(1): 169-174. (PubMed | DOI | Journal | Google Scholar)

Krem, M. M. and Di Cera, E. (2002). "Evolution of enzyme cascades from embryonic development to blood coagulation." Trends in Biochemical Sciences 27(2): 67-74. (PubMed | DOI | Journal | Google Scholar)

Laird, D. J. (2002). "Immune System." Encyclopedia of Evolution. Edited by M. Pagel. Oxford, Oxford University Press. 2: 558-564. (Library | Publisher | Amazon | Google Print)

Lewis, S. M. (1999). "Evolution of Immunoglobulin and T-Cell Receptor Gene Assembly." Annals of the New York Academy of Sciences 870: 58-67. (PubMed | Google Scholar)

Lewis, S. M. and Wu, G. E. (1997). "The origins of V(D)J recombination." Cell 88(2): 159-162. (PubMed | DOI | Journal | Google Scholar)

Lewis, S. M. and Wu, G. E. (2000). "The old and the restless." Journal of Experimental Medicine 191(10): 1631-1636. (PubMed | Journal | Google Scholar)

Litman, G. W., Anderson, M. K. and Rast, J. P. (1999). "Evolution of antigen binding receptors." Annual Review of Immunology 17: 109-147. (PubMed | DOI | Journal | Google Scholar)

Marchalonis, J. J., Adelman, M. K., Schluter, S. F. and Ramsland, P. A. (2006). "The antibody repertoire in evolution: Chance, selection, and continuity." Developmental and Comparative Immunology 30(1-2): 223-247. (PubMed | DOI | Journal | Google Scholar)

Marchalonis, J. J., Hohman, V. S., Kaymaz, H., Schluter, S. F. and Edmundson, A. B. (1994). "Cell Surface Recognition and the Immunoglobulin Superfamily." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 20-33. (Library | PubMed | Google Print)

Marchalonis, J. J., Jensen, I. and Schluter, S. F. (2002). "Structural, antigenic and evolutionary analyses of immunoglobulins and T cell receptors." Journal of Molecular Recognition 15(5): 260-271. (PubMed | DOI | Journal | Google Scholar)

Marchalonis, J. J., Kaveri, S., Lacroix-Desmazes, S. and Kazatchkine, M. D. (2002). "Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system." FASEB Journal 16(8): 842-848. (PubMed | Journal | Google Scholar)

Marchalonis, J. J. and Schluter, S. F. (1994). "Development of an Immune System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 1-11. (Library | PubMed | Google Print)

Market, E. and Papavasiliou, F. N. (2003). "V(D)J Recombination and the Evolution of the Adaptive Immune System." PLoS Biology 1(1): 24-27. (PubMed | DOI | Journal | Google Scholar)

Messier, T. L., O'Neill, J. P., Hou, S.-M., Nicklas, J. A. and Finette, B. A. (2003). "In vivo transposition mediated by V(D)J recombinase in human T lymphocytes." The EMBO Journal 22(6): 1381-1388. (PubMed | DOI | Journal | Google Scholar)

Nonaka, M. (2000). "Origin and evolution of the Complement System." Origin and Evolution of the Vertebrate Immune System. Edited by L. Du Pasquier and G. W. Litman. Berlin, Springer. 248: 37-50. (Library | PubMed | Amazon | Google Print)

Nonaka, M. and Miyazawa, S. (2001). "Evolution of the Initiating Enzymes of the Complement System." Genome Biology 3(1): 1001.1001-1001.1005. (PubMed | DOI | Journal | Google Scholar)

Nonaka, M. and Yoshizaki, F. (2004). "Evolution of the Complement System." Molecular Immunology 40(12): 897-902. (PubMed | DOI | Journal | Google Scholar)

Ohno, S. (1994). "MHC Evolution and Development of a Recognition System." Primordial Immunity: Foundations for the Vertebrate Immune System. Edited by G. Beck, E. L. Cooper, G. S. Habicht and J. J. Marchalonis. New York, New York Academy of Sciences. 712: 13-19. (Library | PubMed | Google Print)

Opal, S. M. (2000). "Phylogenetic and functional relationships between coagulation and the innate immune response." Critical Care Medicine 28(9): S77-S80. (PubMed | Journal | Google Scholar)

Pancer, Z., Amemiya, C. T., Ehrhardt, G. R. A., Ceitlin, J., Gartland, G. L. and Cooper, M. D. (2004). "Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey." Nature 430(6996): 174-180. (PubMed | DOI | Journal | Google Scholar)

Plasterk, R. (1998). "Ragtime jumping." Nature 394(6695): 718-719. (PubMed | DOI | Journal | Google Scholar)

Richards, M. H. and Nelson, J. L. (2000). "The Evolution of Vertebrate Antigen Receptors: A Phylogenetic Approach." Molecular Biology and Evolution 17(1): 146-155. (PubMed | Journal | Google Scholar)

Roth, D. B. (2000). "From lymphocytes to sharks: V(D)J recombinase moves to the germline." Genome Biology 1(2): 1014.1011-1014.1014. (PubMed | DOI | Journal | Google Scholar)

Rothenberg, E. V. and Pant, R. (2004). "Origins of lymphocyte developmental programs: transcription factor evidence." Seminars in Immunology 16(4): 227-238. (PubMed | DOI | Journal | Google Scholar)

Sakano, H., Hüppi, K., Heinrich, G. and Tonegawa, S. (1979). "Sequences at the somatic recombination sites of immunoglobulin light-chain genes." Nature 280(6): 288-294. (PubMed | DOI | Journal | Google Scholar)

Schatz, D. G. (1999). "Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system." Immunologic Research 19(2-3): 169-182. (PubMed | Google Scholar)

Schatz, D. G. (2004). "Antigen receptor genes and the evolution of a recombinase." Seminars in Immunology 16(4): 245-256. (PubMed | DOI | Journal | Google Scholar)

Schluter, S. F., Bernstein, R. M., Bernstein, H. and Marchalonis, J. J. (1999). "'Big Bang' emergence of the combinatorial immune system." Developmental and Comparative Immunology 23(2): 107-111. (PubMed | DOI | Journal | Google Scholar)

Schluter, S. F., Bernstein, R. M. and Marchalonis, J. J. (1997). "Molecular origins and evolution of immunoglobulin heavy-chain genes of jawed vertebrates." Immunology Today 18(11): 543-549. (PubMed | DOI | Journal | Google Scholar)

Stavnezer, J. and Amemiya, C. T. (2004). "Evolution of isotype switching." Seminars in Immunology 16(4): 257-275. (PubMed | DOI | Journal | Google Scholar)

Thompson, C. B. (1995). "New insights into V(D)J recombination and its role in the evolution of the immune system." Immunity 3(5): 531-539. (PubMed | DOI | Journal | Google Scholar)

Vaandrager, J.-W., Schuuring, E., Philippo, K. and Kluin, P. M. (2000). "V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma." Blood 96(5): 1947-1952. (PubMed | Journal | Google Scholar)

van Gent, D. C., Mizuuchi, K. and Gellert, M. (1996). "Similarities between initiation of V(D)J recombination and retroviral integration." Science 271(5255): 1592-1594. (PubMed | Journal | JSTOR | Google Scholar)

Zhou, L., Mitra, R., Atkinson, P. W., Hickman, A. B., Dyda, F. and Craig, N. L. (2004). "Transposition of hAT elements links transposable elements and V(D)J recombination." Nature 432: 995-1001. (PubMed | DOI | Journal | Google Scholar)


Note

During his direct testimony, Plaintiffs' expert Kenneth Miller highlighted eight articles on the development and confirmation of the transposon hypothesis for the evolutionary origin of the adaptive immune system. During the cross-examination of Michael Behe, Miller's list was given to Michael Behe first, followed by the rest of the literature. Miller's eight articles partially overlapped with the list of 58 articles in the Behe cross-examination exhibit; they have been combined to produce the articles list above. Also, a few of the available books were not read into the record, being available only as photocopies, or difficult to explain quickly (i.e. Immunology of Annelids).