An Ancient MHC-linked gene encodes a non-rearranging shark antibody, UrIg, convergent with IgG

• Published in: The Journal of immunology (1950) 2023-09, Vol.211 (6), p.1042-1051
• Main Authors: Flajnik, Martin F., Stanfield, Robyn, Pokidysheva, Elena N., Boudko, Sergei P., Wilson, Ian, Ohta, Yuko
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2300361

Gnathostome adaptive immunity is defined by the antigen receptors, immunoglobulins (Ig) and T cell receptors (TCR), and the major histocompatibility complex (MHC). Cartilaginous fish are the oldest vertebrates with these adaptive hallmarks. We and others have unearthed non-rearranging antigen receptor-like genes in several vertebrates, some of them encoded in the MHC or in MHC paralogous regions. One of these genes, named UrIg, was detected in the class III region of the shark MHC that encodes a protein with typical Variable (V) and Constant (C) domains like those found in conventional Ig and TCR. As no transmembrane region was detected in gene models or cDNAs the protein does not appear to act as a receptor. Unlike some other shark Ig genes, the UrIg V region shows no evidence of RAG-mediated rearrangement, and thus is likely related to other V genes that predated the invasion of the RAG transposon. The UrIg gene is present in all elasmobranchs and evolves conservatively, unlike Ig and TCR. Also, unlike Ig/TCR, the gene is not expressed in secondary lymphoid tissues, but mainly in the liver. Recombinant forms of the molecule form disulfide-linked homodimers, which is the form also detected in many shark tissues by western blotting. mAbs specific for UrIg identify the protein in the extracellular matrix of several shark tissues by immunohistochemistry. We propose that UrIg is related to the V gene invaded by the RAG transposon, consistent with the speculation of emergence of Ig/TCR within the MHC or proto-MHC.