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  • Review Article
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Comparative analyses of immunoglobulin genes: surprises and portents

Nature Reviews Immunology volume 2, pages 688–698 (2002)Cite this article

Key Points

  • The adaptive immune system — defined by clonally distributed antigen receptors, the presence of the recombination-activating genes (RAGs), somatic hypermutation, polymorphic MHC class I and class II molecules, a thymus and secondary lymphoid tissues — is found only in the jawed vertebrates.

  • Affinity maturation in response to hapten antigens is poor for species other than mammals; rather than a change in the affinity of the response of up to four orders of magnitude, at the most, there is only a one–twofold increase in affinity.

  • B cells from cold-blooded vertebrates mutate their antigen-receptor genes but do not form germinal centres after antigen activation. In Xenopus, guanine/cytosine mutations are preferred, but in cartilaginous fish, the mutation process is similar to that in mammals, except for the presence of tandem mutations in IgNAR and light-chain genes and, perhaps, a gene-conversion bias at the heavy-chain locus.

  • Birds and most mammals (the so-called 'gut-associated lymphoid tissue (GALT) species') do not use variable–diversity–joining (VDJ) rearrangement to generate the antibody repertoire, but instead, modify rearranged genes by somatic hypermutation and/or gene conversion in GALT.

  • Cartilaginous-fish immunoglobulin genes have a so-called 'cluster organization', with each cluster containing the rearranging V, (D) and J segments, as well as constant-region exons. Three heavy-chain isotypes and three light-chain isotypes are all encoded by many clusters, and rearrangement does not occur between clusters.

  • Some cartilaginous-fish immunoglobulin genes have been joined by RAG activity in germ cells. When all members of a particular family are joined, the genes are expressed throughout life. When there is a mixture of germ-line-joined and -unjoined genes in an isotype, the germ-line-joined genes are preferentially expressed early in development and then expression is perpetuated only in primary lymphoid tissues.

  • IgD has been detected only in primates and rodents, but an isotype that has similarity to IgD has been found in bony fish. The absence of IgD in GALT-containing species might be important in repertoire generation.

  • The immunoglobulin-isotype switch mechanism arose in an amphibian ancestor, which indicates that somatic hypermutation and gene conversion preceded isotype switching in evolution.

  • Xenopus has an immunoglobulin isotype that is expressed predominantly in mucosal tissue called IgX, which is analogous to mammalian IgA. Furthermore, as for a subset of IgA-producing B cells in mice, the production of IgX is T-cell-independent and its repertoire is predicted to be influenced by gut antigens.

  • Amphibians are the phylogenetically oldest group to have an IgG equivalent, known as IgY, which is also found in reptiles and birds. As the memory B-cell 'burst' that is found in mice has been shown to be dependent on the cytosolic tail of IgG, the presence of a homologous segment in frogs indicates that amphibians might be the oldest group to have 'textbook' B-cell memory.

  • Palindromic sequences near to switch boxes in Xenopus were shown to be involved in the switch mechanism, and, therefore, secondary structure in single-stranded DNA, rather than nucleotide composition, regulates the initial breaks.

  • Somatic hypermutation, gene conversion and isotype switching are all dependent on expression of activation-induced cytidine deaminase (AID). Study of the expression of this gene in ectothermic vertebrates might reveal the 'selecting environments' in secondary lymphoid tissues in which immunoglobulin genes mutate in animals that do not have germinal centres.

  • Most investigators believe that an invasion by a RAG-based transposon into an immunoglobulin-superfamily exon explains the origins of the V(D)J rearrangement system, and that this 'big bang' event was the impetus for emergence of the adaptive immune system. The demonstration that the RAG1 and RAG2 enzymes can transpose DNA that is flanked by recombination signal sequences (RSS) into double-stranded DNA is consistent with this proposal.

  • As the molecules that are involved in somatic hypermutation and gene conversion were apparently derived by a gradual evolutionary process (rather than a horizontal transfer of the RAG transposon) and hypermutation and V(D)J rearrangement are both found in cartilaginous fish, it is possible that the original adaptive immune system was hypermutation- and/or conversion-based.

Abstract

The study of immunoglobulin genes in non-mouse and non-human models has shown that different vertebrate groups have evolved distinct methods of generating antibody diversity. By contrast, the development of T cells in the thymus is quite similar in all of the species that have been examined. The three mechanisms by which B cells uniquely modify their immunoglobulin genes — somatic hypermutation, gene conversion and class switching — are increasingly believed to share some fundamental mechanisms, which studies in different vertebrate groups have helped (and will continue to help) to resolve. When these mechanisms are better understood, we should be able to look to the constitutive pathways from which they have evolved and perhaps determine whether the rearrangement of variable, diversity and joining antibody gene segments — V(D)J recombination — was superimposed on an existing adaptive immune system.

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Figure 1: Evolution of features of the adaptive immune system in vertebrates.
Figure 2: Differences in the formation of the BCR repertoire between human and mouse and the GALT species.

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Acknowledgements

This work is dedicated to the memory of Jeanette. Thorbecke, who was perhaps the scientist who was most instrumental in identifying the function of germinal centres. I thank M. Diaz, L. Du Pasquier, H. Dooley and M. Cooper for reading of the manuscript at different stages. I also thank my colleagues E. Hsu, L. Rumfelt, J. Cerny, C. McKinney and A. Greenberg for helping to formulate some of the ideas that are presented here. I am supported by grants from the National Institutes of Health.

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  1. Department of Microbiology and Immunology, University of Maryland at Baltimore, Room 13-009, 655 West Baltimore Street, Baltimore, 21201, Maryland, USA

    Martin F. Flajnik

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DATABASES

LocusLink

AID

APOBEC1

RAD51B

RAG1

RAG2

TDT

XRCC2

XRCC3

FURTHER INFORMATION

Encyclopedia of Life Sciences

immunoglobulin gene rearrangements

immune response: evolution

immunology: comparative immunology of mammals

somatic hypermutation in antibody evolution

Glossary

SOMATIC HYPERMUTATION

The substitution of 'untemplated' single (or tandem) nucleotides targeted to a rearranged VDJ or VJ segment that occurs only in B cells. The mutations are found between the promoter and enhancer of the rearranged gene. This process occurs in all jawed vertebrates after mature B cells have been stimulated by antigen and helper T cells, but it also occurs at the sheep λ locus and rabbit heavy-chain locus in immature B cells to generate the pre-immune repertoire.

GENE CONVERSION

A homologous recombination event in which the donor gene(s) remains unmodified and an acceptor gene acquires the recombined segment. In chickens, variable (V) pseudogenes are donors that modify the functional, rearranged V gene in bursal follicles to generate a diverse pre-immune repertoire.

CLASS-SWITCH RECOMBINATION

The mechanism by which a functional VDJ segment in mammalian antigen-stimulated B cells is rearranged by a deletional mechanism from upstream of the μ gene to upstream of a γ, ɛ or α heavy-chain gene. The effector function of the secreted B-cell receptor post-switch is changed without the modification of antibody specificity. Although all vertebrates have many immunoglobulin isotypes, only the tetrapods (amphibians, reptiles, birds and mammals) have the isotype-switch mechanism.

VERTEBRATES

Animals that have a dorsal hollow nerve cord, gill slits derived from all three germ layers, a dorsal notochord and a postanal tail at some time during their lives. There are only two living species of jawless vertebrate, the lamprey and hagfish. Only the jawed vertebrates (gnathostomes), including cartilaginous fish, bony fish, amphibians, reptiles, birds and mammals, have an adaptive immune system.

GERMINAL CENTRE

A structure that is found in the follicles of secondary lymphoid tissues that is composed of proliferating B cells that are induced to undergo somatic hypermutation. B cells that have modified B-cell receptors that cannot bind to antigen die by apoptosis, whereas those that do bind are positively selected to exit the germinal centre as memory cells. Although all vertebrates have secondary lymphoid tissues that contain B-cell follicles (at least, accumulations of B cells), only birds and mammals can form germinal centres.

AFFINITY MATURATION

The mutation of antibody variable (V)-region genes followed by selection for higher-affinity variants in the germinal centre leads to an increase in average antibody affinity as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with each other to capture decreasing amounts of antigen.

V(D)J RECOMBINATION

The recombination-activating gene (RAG)-dependent somatic rearrangement of variable (V), diversity (D) (in heavy-chain genes) and joining (J) regions of antigen-receptor-encoding genes, which is responsible for the repertoire diversity of T-cell receptors in all vertebrates and of B-cell receptors in all non-GALT species.

HAPTENIC ANTIGEN

A molecule that can bind antibody but cannot by itself elicit an immune response. Antibodies that are specific for a hapten can be generated when the hapten is chemically linked to a protein carrier that can elicit a T-cell response.

COMPLEMENTARITY-DETERMINING REGIONS

Amino acids that are found in three areas of each of the heavy and light chains that physically contact antigen; that is, they are complementary to the antigen.

HOTSPOT

Frequently mutated G or C nucleotides in RGYW or WRCY motifs, respectively.

RECOMBINATION SIGNAL SEQUENCE

A sequence adjacent to germ-line V, D and J segments that is required for RAG-mediated rearrangement of such segments. An RSS is composed of a heptamer directly adjacent to the rearranging segment followed by a spacer of 12 or 23 nucleotides and then a nonamer. Rearrangement occurs only between RSSs with 12- and 23-nucleotide spacers.

TRANSPOSABLE ELEMENTS

Segments of genomic DNA of ancient origins that are acquired generally by horizontal transfer and can move from one chromosomal location to another.

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Flajnik, M. Comparative analyses of immunoglobulin genes: surprises and portents. Nat Rev Immunol 2, 688–698 (2002). https://doi.org/10.1038/nri889

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