A more fundamentally different organization of immunoglobulin genes is found in the cartilaginous fish, the most primitive jawed vertebrates. Sharks have multiple copies of discrete VL–JL–CL and VH–DH–JH–CH cassettes, and activate rearrangement within individual cassettes (Fig. 5.28). Although this is somewhat different from the kind of combinatorial gene rearrangement of higher vertebrates, in most cases there is still a requirement for a RAG-mediated somatic rearrangement event. As well as rearranging genes, cartilaginous fish have multiple ‘rearranged’ VL regions (and sometimes rearranged VH regions) in the germline genome (see Fig. 5.28) and apparently generate diversity by activating the transcription of different copies. Even here, some diversity is also contributed by combinatorial means by the subsequent pairing of heavy and light chains.
This ‘germline-joined’ organization of the light-chain loci is unlikely to represent an intermediate evolutionary stage, because in that case the heavy-chain and light-chain genes would have had to independently acquire the capacity for rearrangement by convergent evolution. It is much more likely that, after the divergence of the cartilaginous fishes, some immunoglobulin loci became rearranged in the germline of various ancestors through activation of the RAG genes in germ cells, with the consequent inheritance of the rearranged loci by the offspring. In these species, the rearranged germline loci might confer some advantages, such as ensuring rapid responses to common pathogens by producing a preformed set of immunoglobulin chains.
The IgM antibody isotype is thought to go back to the origins of adaptive immunity. It is the predominant form of immunoglobulin in cartilaginous
Fig. 5.28 The organization of immunoglobulin genes is different in different species, but all can generate a diverse repertoire of receptors.
The organization of the immunoglobulin heavy-chain genes in mammals, in which there are separated clusters of repeated V, D, and J gene segments, is not the only solution to the problem of generating a diverse repertoire of receptors. Other vertebrates have found alternative solutions. In ‘primitive’ groups, such as the sharks, the locus consists of multiple repeats of a basic unit composed of a V gene segment, one or two D gene segments, a J gene segment, and a C gene segment. A more extreme version of this organization is found in the κ-like light-chain locus of some cartilaginous fishes such as the rays and the carcharhine sharks, in which the repeated unit consists of already rearranged VJ–C genes, from which a random choice is made for expression. In chickens, there is a single rearranging set of gene segments at the heavy-chain locus but there are multiple copies of pre-integrated VH–D segment pseudogenes. Diversity in this system is created by gene conversion, in which sequences from the VH-–D pseudogenes are copied onto the single rearranged VH gene.
fishes and bony fishes. The cartilaginous fishes also have at least two other heavy-chain isotypes not found in more recently evolved species. One, IgW, has a constant region composed of six immunoglobulin domains, whereas the second, IgNAR, which we described in Section 4-10, seems to be related to IgW but has lost the first constant-region domain and does not pair with light chains. Instead, it forms a homodimer in which each heavy-chain V domain forms a separate antigen-binding site. IgW seems to be related to IgD (which is first found in bony fish) and, like IgM, seems to go back to the origin of adaptive immunity.
5-21 Both α:β and γ:δ T-cell receptors are present in cartilaginous fishes.