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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Marino, Pamela
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Scripps Research Institute
La Jolla
United States
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