Isotype Exclusion and Hypermutation in the Nurse Shark

Suny Downstate Medical Center, Brooklyn NY

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Abstract

DESCRIPTION (provided by applicant): Sharks and skates are representatives of the earliest vertebrates with an immune system based on immunoglobulin (Ig) receptors that diversify by gene rearrangement and somatic mutation. The recognition motifs and enzymatic machinery involved in the two processes point to mechanistically unrelated pathways that arose independently. We hypothesize that, before sharks, the prototype antigen receptor may have diversified only by mutation; the mechanism of rearrangement became introduced later in evolution and is not an intrinsic part of the regulatory process for expression. We propose to: (1) investigate the role of rearrangement in the shark, which carries multiple Ig loci and germline-rearranged genes. We will establish whether the shark Ig receptors are clonally expressed, if there is a hierarchy of activation among the many loci, and if productive rearrangements, germline or somatic, feed back to modulate expression of others. (2) investigate a novel mechanism in L chain mutants, non-templated insertion. Our goal is to examine the patterns of change to determine how such structures are formed during the hypermutation process. We will also study H chain mutation, to obtain a comprehensive picture of somatic hypermutation in one species of this early vertebrate. The information emerging from this research will provide new understanding for the evolution of mechanisms for antibody diversification and the rearrangement process and give insight into the emergence of a specific, clonal recognition of the pathogenic non-self.