Placoderm A few years ago, one of the aspects of the immune system that puzzled me most was the shark immune system. It’s not that sharks have an immune system; everything has some form of resistance against parasites, or else they don’t exist any more. Nor is it surprising that sharks’ immune systems are really pretty similar to ours: They have T cell receptors that are generated through somatic recombination, they have MHC class I and II, they have T cells and B cells and a thymus — not to mention all the innate stuff that is also pretty similar. But sharks are really not all that far away from us, evolutionarily speaking, so it’s not astonishing that their immune systems are not far away either.

What was astonishing to me is that this all (apparently) arrived all at once. Lampreys and hagfish, with a common ancestor not far from sharks, did not (I thought) have any of those things. All the pieces, that need to fit precisely with each other to work at all, arose from nothing — an immunological Big Bang.1 That’s not how evolution is supposed to work.

I assured myself that this just seemed puzzling, and probably once people started looking more closely at lamprey or hagfish immunity we would find that the common ancestor really did have some of these things, that were co-opted into the jawed-vertebrate immune system. And in the past five years or so, that’s pretty much what has happened. We are still in early days of lamprey immunology, but already we can see much of the foundation of the shark (and our) immune systems there. Sea urchins (which have a common ancestor with lampreys) have molecules that are much like RAG. Lampreys have cells that are very lymphocyte-like.2 These cells accumulate in a region that looks quite thymus-like. Lampreys even have a proto-T cell receptor, and something very CD4-like,3 although as far as I know no MHC-like molecules have yet been identified.

Lamprey So lampreys have most, if not all, of the requirements for an adaptive immune system. In fact, lampreys apparently do have an adaptive immune system. The hallmark of an adaptive immune system is immunological memory, and lampreys act as if they have immune memory (though it’s not as fast as ours), responding more rapidly to antigens on a second exposure, 4 although I think some of the caveats that apply to the “insect immune memory” observations apply here as well.5

And yet there is still one big surprise. The most interesting part of the lamprey immune system is not so much the similarities to jawed vertebrates: it’s the differences. In sharks and their children, unto us, lymphocytes (T cells and B cells) make tremendously diverse receptors that can interact specifically with antigens. This diversity is produced using RAG recombination to make T cell receptors and antibodies. Lampreys also make an equally diverse, antigen-recognizing receptor in their lymphocytes — but their receptors look nothing like ours, and are generated using an entirely different system of somatic rearrangement!

Kim et al Fig 5 The antigen-specific receptor on lamprey (and hagfish) lymphocytes6 is called a “VLR” (variable leukocyte receptor), and it is not related in the least to TcRs or antibodies; both of the latter are built on the immunoglobulin fold, while VLRs are made of leucine-rich repeats that produce the characteristic horseshoe shape of an LRR. (Toll-like receptors are also members of the LRR family, so I wondered about the possibility of a TLR-like molecule having been co-opted from an innate to an adaptive role. But apparently VLRs are members of a different family of LRRs than are TLRs,7 being more similar to some platelet receptors in humans.) VLRs are, as I say, enormously diverse, at least as variable as are TLRs, and just as with TcRs their variable recgions are clustered, in what seems to be the antigen-recognition region (the figure at left, from Kim et al., 8 is of a hagfish VLR, with the variable regions indicated in red; click for a larger version.) Like TcRs, their diversity arises through DNA shuffling in somatic cells. But the mechanism of shuffling is different, involving combinatorial use of a large number of cassettes, or modules — some 2000 of them. 9

Blogging on Peer-Reviewed ResearchBut there’s more! This mechanism of diversity in lampreys, which really is quite different from the TcR mechanism of recombination? It uses a cytosine deaminase! Why is that interesting? 7 Because a related cytosine deaminase (AID-APOBEC) is involved in human immunoglobulin class switching and maturation! 10 So even though lampreys have developed a different mechanism of receptor diversity, they (and therefore, probably, our common ancestors) use some of the same molecules that we use in our receptor diversity system.

Five years ago, it seemed that the shark immunological Big Bang came out of nowhere. Now — exactly as we’d expect from evolution — we know that sharks adapted pre-existing systems, and that rather than a Big Bang there was more like a gradual accumulation of pieces that added up to a revolution.


  1. 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. Proc Natl Acad Sci U S A 93, 9454-9459.[]
  2. Shintani, S., Terzic, J., Sato, A., Saraga-Babic, M., O’hUigin, C., Tichy, H., and Klein, J. (2000). Do lampreys have lymphocytes? The Spi evidence. Proc Natl Acad Sci U S A 97, 7417-7422.
    and
    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. Proc Natl Acad Sci U S A 99, 14350-14355.
    and especially
    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. Proc Natl Acad Sci U S A 99, 14356-14361. []
  3. Pancer, Z., Mayer, W. E., Klein, J., and Cooper, M. D. (2004). Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc Natl Acad Sci U S A 101, 13273-13278. []
  4. For example — I haven’t read these articles directly, but they are regularly cited in more recent papers — Perey, D. Y., Finstad, J., Pollara, B. & Good, R. A. Evolution of the immune response. VI. First and second set skin homograft rejections in primitive fishes. Lab. Invest. 19, 591-597 (1968)
    and
    Fujii, T., Nakagawa, H., and Murakawa, S. (1979). Immunity in lamprey. I. Production of haemolytic and haemagglutinating antibody to sheep red blood cells in Japanese lampreys. Dev Comp Immunol 3, 441-451.[]
  5. But not all, because as you will see a mechanistic explanation for lamprey memory is taking shape.[]
  6. Pancer, Z., Amemiya, C. T., Ehrhardt, G. R., Ceitlin, J., Gartland, G. L., and Cooper, M. D. (2004). Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174-180. []
  7. Rogozin, I. B., Iyer, L. M., Liang, L., Glazko, G. V., Liston, V. G., Pavlov, Y. I., Aravind, L., and Pancer, Z. (2007). Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat Immunol 8, 647-656. [][]
  8. Kim, H. M., Oh, S. C., Lim, K. J., Kasamatsu, J., Heo, J. Y., Park, B. S., Lee, H., Yoo, O. J., Kasahara, M., and Lee, J. O. (2007). Structural diversity of the hagfish variable lymphocyte receptors. J Biol Chem 282, 6726-6732. []
  9. Nagawa, F., Kishishita, N., Shimizu, K., Hirose, S., Miyoshi, M., Nezu, J., Nishimura, T., Nishizumi, H., Takahashi, Y., Hashimoto, S., Takeuchi, M., Miyajima, A., Takemori, T., Otsuka, A. J., and Sakano, H. (2007). Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice. Nat Immunol 8, 206-213.
    and
    Rogozin, I. B., Iyer, L. M., Liang, L., Glazko, G. V., Liston, V. G., Pavlov, Y. I., Aravind, L., and Pancer, Z. (2007). Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat Immunol 8, []
  10. Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. (2000). Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553-563. []