This is a renewal application of an R01 grant to study B cell tolerance in health and autoimmunity. The focus here is on peripheral B cell tolerance. Several lines of evidence, including prior work on this grant, have shown that peripheral B cell tolerance occurs and is presumably a barrier to the development of autoimmune disease. The consensus conceptual framework to explain B cell tolerance is the 2-signal model of Bretcher and Cohn, which posits that in the absence of T cell help, BCR stimulation is a negative signal for B cells. However, this model fails to explain how B cells can respond to T-independent type II (TI-2) antigens or distinguish TI-2 antigens from multimeric self determinants. In the present grant an alternative model is offered, which proposes that B cells express inhibitory coreceptors that aid in making this distinction. This """"""""self marker"""""""" hypothesis will be tested through the following Specific Aims: 1. Determine the differences between TI-2-responsive and -non-responsive B cell populations in terms of their gene expression and ability to undergo peripheral deletion. 2. Determine if disruption of putative self-marker signals inhibits peripheral deletion. The long-term goal of these studies is to understand how the self/non-self discrimination is made, what goes wrong in the development of autoimmunity, and to identify ways that these mechanisms may be manipulated to ameliorate or prevent disease.
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