Self-reactivity has concerned immunologists since the time of Ehrlich who referred to this potential problem as horror autotoxicus. Landsteiner's finding that the immune repertoire is almost infinitely diverse focused the problem on how such diversity could be generated while avoiding self-reactivity. We now understand that antibody diversity is produced by V(D)J recombination, and transgenic experiments have shown that at least three mechanisms account for silencing of self-reactive antibodies during B cell development in the bone marrow: receptor editing, deletion, and anergy. Experiments performed in the last funding period showed that B cells are targeted for receptor editing during a 2-hour delay in development at the pre-BII cell stage during which RAG1 and RAG2 expression persist. Most important we found that approximately 25% of all antibody molecules are produced by gene replacement and that editing requires antibody gene transcription. But despite the potential impact of receptor editing in maintaining B cell tolerance the regulation of editing and role of auto-reactivity in inducing editing have not been determined. The long-range goal of the proposed research is to elucidate the physiologic function and regulation of receptor editing in developing B cells. The working hypothesis is that self-reactivity induces receptor editing and that cis element that regulate RAG expression account for the differences in receptor editing between T and B cells. The first part of the project will make use of indicator mouse strains that carry human Ck to determine why so many B cells edit their receptors and to examine the role of transcription in regulating receptor editing. The second part of the project will try to define the cis elements for RAG regulation in vivo. These studies have significant implications for understanding how B cells and T cells produce their receptors and maintain tolerance in vivo.
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