This is a renewal application to study the molecular basis for B cell negative selection and tolerance. The ability of the immune system to discriminate between self and non-self antigens requires a central process to facilitate the functional or physical elimination of self-reactive lymphocytes early after they acquire athe ability to recognize and respond to antigen. Despite considerable support for B cell negative selection at the cellular level, the molecular basis for this process among immature stage B cells remains unexplored. The central hypothesis of the proposed studies is that there are developmentally-regulated differences in BCR signal transduction between immature and mature B cells that account for the intrinsic unresponsiveness and negative selection associated with antigen recognition by immature-stage B cells. Our previously funded studies were focused ont he identification of differences in BCR signal transduction between mature- and immature-stage B cells that are related to the intrinsic activation unresponsiveness of immature B cells to BCR signalling. We have identified a series of specific developmentally- related differences in components associated with the BCR in immature and mature B cells t hat we believed are related to the uncoupling of BCR from a second messenger pathway critical to activation of B cells in response to BCR signalling. The focus of this renewal application will be to establish the molecular basis for the uncoupling of the BCR from this second messenger pathway at the immature stage of B cell development and to establish the relevance of differential BCR signal transduction on negative selection. Specifically, we propose to: (1) determine the relationship between BCR-induced apoptosis and the inability to induce inositol phospholipid hydrolysis in immature-stage B cells; (2) define the role of fgr expression and activation in BCR signaling in mature B cells; (3) define the molecular mechanism involved in coupling the BCR to PLCg phosphorylation and activation in mature B cells and determine the mechanism by which this process is uncoupled in immature-stage B cells; and, (4) evaluate athe influence of expression of specific regulators of apoptosis on immature- and mature-stage B cell responsiveness to BCR signaling. These studies are of relevance to our understanding of processes leading to autoimmunity and malignant transformation of lymphocytes; inability to accomplish negative selection results in the generation of self reactive lymphocytes that can operate in autoimmune diseases or be chronically stimulated by self-antigen, resulting in malignancies such as CLL.
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