PLCgammas in B Cell Biology and Autoimmunity

描述(申请人提供)：由B细胞受体(BCR)转导的信号通过控制克隆缺失、受体编辑和无能来调节B细胞对自身抗原的耐受性。介导B细胞耐受的BCR信号还不完全清楚，而引起B细胞耐受崩溃和随之而来的自身免疫性疾病的BCR信号的改变更是知之甚少。磷脂酶C-γ(PLC-γ)是一种对bcr信号转导起关键作用的脂酶，它能产生二酰基甘油和1，4，5-三磷酸肌醇，分别激活PKC？和钙/钙调神经磷酸酶途径。PLCγ有两种异构体，即PLCγ1和PLCγ2。在此之前，我们报道了PLCγ2介导的PKC？/bcl10/tak1/ikk/nf-kB信号通路在B细胞成熟和激活、免疫球蛋白轻链位点激活和bcr受体编辑中起关键作用。由于PLCγ1缺乏导致早期胚胎死亡，我们建立了条件性PLCγ1基因敲除小鼠，发现B细胞特异性缺失PLCγ1削弱了bcr信号转导并阻止了这些小鼠B细胞无能的维持。这些新数据揭示了PLCγ1在建立自我宽容方面的关键但被低估的作用。这些发现的临床相关性是，PLC Gγ突变改变了bcr信号，并在人类患者中引发免疫缺陷和自身免疫性疾病。因此，PLCγ通路在控制小鼠和人类的B细胞耐受中起着至关重要的作用。这一更新应用的主要目的是研究PLCγ依赖的途径将bcr信号的微小数量变化转化为B细胞的质量变化，从而使其进入无能状态的分子机制。具体地说，我们将1)确定PLCγ1调节B细胞无能的分子机制，2)研究一种新的分子如何控制PLCγ及其下游途径来调节B细胞无能。这种基于机制的研究将从概念上促进我们对自身抗原调节B细胞无能的分子信号机制的理解。对人类自身免疫性疾病分子发病机制的新见解可能会为其中某些疾病找到新的靶向治疗方法。

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.