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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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Immunobiology: The Immune System in Health and Disease. 5th edition.

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Evolution of the adaptive immune response

The evolution of adaptive immunity is one of the greatest biological enigmas of all time. For a long time, the origin of adaptive immunity was shrouded in mystery, but the fog is surely rising and a clear picture is beginning to emerge. As we will see in this part of the chapter, the evolution of adaptive immunity appears to have been made possible by the invasion of a putative immunoglobulin-like gene by a transposable element, almost certainly a retroposon. This conferred on the ancestral gene the ability to undergo gene rearrangement, and thus generate diversity. There are, however, still many unanswered questions, and probably many others that have not yet been thought of. The first key question is what was the nature of the piece of DNA that was invaded? It must have resembled a member of the immunoglobulin gene superfamily, and may have already been functioning as some type of antigen receptor, for it to operate appropriately in its changed form; this narrows the field considerably. Second, what was the nature of the cell in which this receptor was expressed? The retroposon itself must have integrated into the host DNA within a germ cell, in order for the two genes RAG-1 and RAG-2 to be inherited together with their targets, called recognition signal sequences, or RSS for short. As RAG-1 and RAG-2 are inherited as a tightly linked pair of genes, while there are at least seven locations to which the ends of the retroposon dispersed (these are the T-cell receptor α, β, γ, and δ chain loci plus the immunoglobulin H, κ, and λ loci), there must be powerful positive selection for these to persist, and that suggests that there was a significant advantage to the organism in expressing a somatically rearranging receptor. What then was the function of this receptor and the function of the cell type in which it was expressed, that could then make good use of this new diversity in recognition? It must have been something like a lymphocyte, but was it more like a macrophage, a polymorphonuclear leukocyte, an NK cell, or some other cell unlike a lymphocyte that no longer exists in vertebrates? And finally, how did the signaling machinery that we learned about in Chapter 6 develop to support this new device, a receptor gene that could rearrange its gene segments? The answers to these questions will, I predict, fill thousands of papers in the years to come.

Adaptive immunity appears abruptly in the cartilaginous fish

It has been known for at least 50 years that all jawed fish can mount an adaptive immune response. On the other hand, hagfish and lampreys, which are jawless vertebrates, lack all signs of an adaptive immune system: they do not have organized lymphoid tissue, they lack primary immune responses, and most importantly, they do not exhibit immunological memory. By contrast, even cartilaginous fish, the earliest jawed fish to survive to the present day, have organized lymphoid tissue, albeit primitive, T-cell receptors and immunoglobulins, and the ability to mount adaptive immune responses. What makes the two phylogenetically related groups so different? And why are they so different? That is the mystery of the evolution of adaptive immunity, and what a mystery it is!

It was only in 1998 that the answers to these questions began to become apparent. In jawed fish and all ‘higher’ vertebrates, adaptive immunity is possible because of what I like to think of as the immunological ‘Big Bang,’ which occurred in some ancestor of the jawed fish. A transposable element invaded a stretch of DNA, presumably a gene that was similar to an immunoglobulin gene or a T-cell receptor gene, and rapidly segregated the transposon sequences encoding the recombinase enzymes used for the invasion from the recognition sequences for these enzymes (Fig. 2). These remnants of the original transposon became the recombination signal sequences of immunoglobulin and T-cell receptor genes. Invasion by a retrotransposon had been speculated on for years as an explanation of the presence of the RAG genes, which encode recombination enzymes essential for the rearrangement of immunoglobulin and T-cell receptor genes (see Chapter 4). Like other retroposons, RAG genes lack introns. The action of RAG proteins at the recognition signal sequences was well known for many years. But it was only in 1998 that two laboratories, working independently, came to the startling conclusion that they had their hands on the key discovery to explain the origin of immunoglobulin and T-cell receptor rearrangement.

Figure 2. The integration of a transposable element into a cell-surface receptor gene was the event that ultimately gave rise to the immunoglobulin and T-cell receptor genes and their somatic recombination.

Figure 2

The integration of a transposable element into a cell-surface receptor gene was the event that ultimately gave rise to the immunoglobulin and T-cell receptor genes and their somatic recombination. Transposable elements are closed circles of extra chromosomal (more...)

The discovery was that the present-day RAG proteins can indeed catalyze a transposition event. While conducting experiments to look at the enzyme mechanisms involved in gene rearrangement, researchers in two independent laboratories, using different assays, both noticed that the stretch of DNA containing the recombination signal sequences was being inserted into other DNA fragments, a process identical to that of transposition (see Fig. 2). This simultaneous discovery was no accident but, as often happens in science, the result of having two very smart people working on the same important problem. The discoveries were published in the same month in two leading journals (and should, I believe, qualify the two scientists leading the two independent groups for a Nobel Prize).

Gene rearrangement is used to control gene expression

One need only turn back to the earlier chapters on adaptive immunity (see Chapters 3-7), where we described the almost infinite variability of the antigen receptors and how it is achieved by gene rearrangement, to see how important gene rearrangement is. And why is it key? Without it, there would be no variable antigen receptors and no possibility of clonal selection—and thus no adaptive immunity.

The discovery of gene rearrangement as a universal generator of diversity solved one of the great early mysteries of immunology: how could the in formation in a human, mouse, or fish genome encode so many unique proteins—the immunoglobulins and T-cell receptors? There were heated discussions during annual workshops about whether the entire repertoire could be encoded in the germline, or whether some genetic trick that had only been seen in immunoglobulins (at that date) would turn out to be true for T-cell receptors as well. Eventually, the molecular genetic discoveries of Susumu Tonegawa and others put this debate to rest.

But the discovery of rearranging gene segments raised other issues about the control of gene expression. How could one go from a silent V gene segment to one that produced a protein just by rearranging it? The answer we give in this book, which is accepted by most, but not all, immunologists, is that gene rearrangement also controls gene expression, and so can do the whole job alone. That raises further problems, which were dealt with in Chapter 7, such as how can the same enzymes work on different genes in T cells and B cells, thus producing T-cell receptors in one and immunoglobulins in the other. This discrimination is now thought to be a function of the different transcription factors produced by early B cells and early T cells, which open up different parts of the chromosomes and make them accessible to the recombination enzymes. Those produced in early B-lineage cells operated on early B cells to produce surface immunoglobulin receptors, and not on T cells, and vice versa.

Animals generate antigen receptor diversity in many different ways

Most animals that we are familiar with generate a large part of their antigen receptor diversity as humans do, by putting together gene segments in different combinations, as described in earlier chapters. However, we noted a few exceptions in passing (see Section 4-10), and it is useful to return to these now and see how far they violate the law that gene segments must be joined according to very strict rules. These rules are the 12/23 rule of gene segment joining, and the requirement for RAG proteins (see Chapter 7). The requirement for RAG proteins is essentially absolute. Mice and people who lack RAG proteins have a total absence of immunoglobulin and T-cell receptors, as manifest in Omenn's syndrome, a human disease that is caused by the mutations in one or the other RAG protein. The 12/23 rule is more subtle, and to my knowledge no patient has been discovered with a deficiency in this rule, but it would be expected to give a phenotype much like that in Omenn's syndrome.

These examples from patients tell us that our ideas about the importance of genes and proteins that we learned about in mice are generally true for humans as well. We must not, however, be too confident that every lesson learned from mice will immediately apply to humans or to other species, since there are many examples where that is not the case.

Some animals use gene rearrangement to always join together the same V and J gene segment initially, and then go on to diversify this recombined V region in various ways. In chickens and rabbits, the recombined V region is diversified by gene conversion (see Section 4-10) in the bursa of Fabricius (in chickens) or another intestinal lymphoid organ (in rabbits) (Fig. 3). Other animals generate their diverse repertoire mainly by somatic hypermutation of a fairly invariant recombined V region, as does the sheep in its ileal Peyer's patch. Some primitive fish have multiple copies of discrete VL-JL-CL and VH-DH-JH-CH cassettes, and activate rearrangement in different copies, while carcharine sharks have multiple ‘rearranged’ VL regions in the germline genome and apparently generate diversity by activating transcription of different copies. All these animals have survived in a hostile environment because they have the other benefit of adaptive immunity, namely, immunological memory. This is the single greatest advantage conferred on animals that have rearranging gene segments, and is the focus of the next part of this chapter.

Figure 3. The organization of immunoglobulin genes is different in different species, but all are capable of generating a diverse repertoire of receptors.

Figure 3

The organization of immunoglobulin genes is different in different species, but all are capable of generating a diverse repertoire of receptors. . The organization of the immunoglobulin heavy-chain genes in mammals, where there are separated clusters (more...)


Gene rearrangement has been known since the early 1970s, and the ‘immunological Big Bang’ has been known for about a few years. Although these two events well explain the development of adaptive immunity, in the next section we will learn about the enormous value that immunological memory has for preserving the two genetic elements of adaptive immunity: recognition signal sequences and RAG proteins. Gene rearrangement is the result of a chance insertion of a retroposon into an unknown cell that must have been either a sperm or an ovum, as it is inserted in the germline. Somehow, still not explained adequately, this retroposon had the good luck to invade a member of the immunoglobulin gene family, and to carry its invasive ends that allow retroposons to move from cell to cell into the right place in the target primordial immunoglobulin gene. At the same time, the RAG genes were preserved, presumably from the same retroposon, but were carried by a different chromosome. These two events, which allowed adaptive immunity to occur, also made immunological memory possible, but they did not make it necessary. Therefore, we ask in the next section of this chapter how immunological memory evolved. What were the evolutionary forces acting on the immune system that not only guaranteed the survival of the species that were lucky enough to inherit this trait, but expanded them to the multitudes that occupy the Earth's surface? And what contribution did the possession of immunological memory make to the ability of vertebrates to occupy most of the ecological niches currently present (although we should not forget that insects and many other invertebrates cohabit with us)?

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2001, Garland Science.
Bookshelf ID: NBK27108


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