Comparative analyses of immunoglobulin genes: surprises and portents

Top Cited Papers
Publisher Website
Google Scholar
Abstract
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.