Signal Transduction in B cell Activation

描述（由申请人提供）：免疫系统的一个关键特征是

DESCRIPTION (provided by applicant): A critical feature of the immune system is its ability to distinguish between self and nonself seemingly ignoring self antigens while responding to and eliminating potential pathogens. Failure of this discrimination can result in autoimmunity. While, auto-reactive antigen receptors are clearly encoded in the genome, cells expressing these receptors are silenced by a variety of mechanisms. In the B cell compartment this occurs by antigen induced editing of receptors to change specificity, deletion by apoptosis, anergy and CD5 dependent hyporesponsiveness In the latter two cases, cells remain viable and competent to bind antigen, but antigen receptor signaling is altered. The long-term objectives of the application are to elucidate the molecular mechanisms underlying the antigen hyporesponsiveness of anergic B cells and peritoneal CD5+ cells. Specific Aims are to elucidate the biochemical underpinning and biological functions of three specific mechanisms of signal modulation revealed by studies conducted during the last funding period. Two of these mechanisms, active in anergic B cells, involve (1) destabilization of the antigen receptor preventing normal transmission of signals from membrane immunoglobulin to Ig-alpha/Ig-beta dimers which function as the receptor's transmembrane transducer, and (2) activation of a negative feedback regulatory loop involving the inositol 5 phosphatase SHIP and the linker Downstream of kinase, Dok. A third mechanism, apparently operative only in peritoneal CD5+ cells, is an inhibitory loop involving Lck, CD5 and SHP-2 and targets BLNK (SLP-65). The proposed studies will be pursued using multiple lymphoma and animal models, but will rely principally on the newly described Ars/A 1 transgenic model of anergy and the VH 11 VK9 transgenic model of CD5+ B 1 cells. They will involve genetic manipulation and a variety of biochemical and biological assays of signal transduction and cellular responses. These studies may reveal drug discovery targets for autoimmunity and immunodeficiency.