Antibody repertoire development in cartilaginous fish

There are 3 H chain and 3 L chain isotypes in the cartilaginous fish, all encoded by genes in the so-called cluster (VDDJ, VJ) organization. The H chain isotypes IgM and IgNAR, are readily detected at the protein level in most species. The third is readily identified at the protein level in skates (IgR) but only via immunoprecipitation or at the transcript level in sharks (IgW). High levels of diversity in CDR3 and up to 200 germline genes have been detected for IgM depending upon the species examined. IgNAR displays very high levels of CDR3 diversity but almost none in the germline. At least IgNAR and L chain genes have been shown to hypermutate to very high levels, apparently in response to antigen. The mutation footprints are similar to those in mammals except that the shark genes uniquely mutate nucleotide residues in tandem. A conspicuous feature of cartilaginous fish Ig genes is the presence of germline-joined genes, which are a result of RAG activity in germ cells. Such genes are expressed early in ontogeny and then extinguished or expressed at lower levels. 19S IgM and IgW expression precede that of 7S IgM and IgNAR during ontogeny. The 'switch' from 19S to 7S IgM, the regulation of expression of the Ig clusters, and the microenvironments for mutation/selection of cartilaginous fish B cells are all areas of ongoing research.