PLCgammas in B Cell Biology and Autoimmunity

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DESCRIPTION (provided by applicant): Signals transduced by the B cell receptor (BCR) regulate B cell tolerance to self-antigens by controlling clonal deletion, receptor editing and anergy. BCR signals that mediate B cell tolerance are not fully understood, and altered BCR signaling that elicits the breakdown of B cell tolerance and consequent autoimmune disease is even less well understood. Stimulation of phospholipase Cγ (PLCγ), a lipid enzyme critical for BCR signaling, generates diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) that activate the PKCß and Ca2+/ calcineurin pathways, respectively. PLCγ has two isoforms, PLCγ1 and PLCγ2. Previously, we reported a key role for the PLCγ2-mediated PKCß/Bcl10/TAK1/IKK/NF-kB signaling pathway in B cell maturation and activation, immunoglobulin light chain locus activation, and BCR receptor editing. As PLCγ1 deficiency causes early embryonic death, we generated conditional PLCγ1 knockout mice, and discovered that B cell-specific deletion of PLCγ1 impairs BCR signaling and precludes the maintenance of B cell anergy in these mice. These new data reveal a pivotal yet under-appreciated role for PLCγ1 in the establishment of self-tolerance. The clinical relevance of these findings is that PLCgγ mutations alter BCR signaling and elicit immunodeficiency and autoimmune diseases in human patients. Thus, the PLCγ pathway plays an essential role in controlling B cell tolerance in both mice and humans. The primary objective of this renewal application is to study the molecular mechanism by which the PLCγ-dependent pathway converts a small quantitative change in BCR signaling into qualitative changes in B cells that drives them into a state of anergy. Specifically, we will 1) determine the molecular mechanism by which PLCγ1 regulates B cell anergy, and 2) study how a novel molecule controls PLCγ and its downstream pathways to regulate B cell anergy. This mechanism-based research will conceptually advance our understanding of the molecular signaling mechanism by which self- antigens regulate B cell anergy. Novel insight into the molecular pathogenesis of human autoimmune disease may identify novel target therapeutics for certain of these diseases.