PLCgammas in B Cell Biology and Autoimmunity

描述（由申请人提供）：B细胞受体（BCR）转导的信号通过控制克隆缺失、受体编辑和能量来调节B细胞对自身抗原的耐受性。介导B细胞耐受性的BCR信号尚不完全清楚，而引起B细胞耐受性破坏和随之而来的自身免疫性疾病的BCR信号改变则更不清楚。磷脂酶Cγ (PLCγ)是一种对BCR信号传导至关重要的脂质酶，刺激它可以产生二酰基甘油（DAG）和肌醇1,4,5-三磷酸（IP3），它们分别激活PKCß和Ca2+/钙调磷酸酶途径。PLCγ有两个同工异构体，PLCγ1和PLCγ2。之前，我们报道了plc γ2介导的PKCß/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受体编辑中的关键作用。由于PLCγ1缺乏会导致早期胚胎死亡，我们产生了条件PLCγ1敲除小鼠，并发现B细胞特异性缺失PLCγ1会损害这些小鼠的BCR信号传导并阻止B细胞能量的维持。这些新数据揭示了plc - γ - 1在建立自我耐受性方面的关键作用，但未被充分认识。这些发现的临床相关性是plcγ突变改变BCR信号并引发人类患者的免疫缺陷和自身免疫性疾病。因此，在小鼠和人类中，PLCγ通路在控制B细胞耐受性中起着重要作用。这项更新应用的主要目的是研究plc γ依赖通路将BCR信号的微小定量变化转化为B细胞的质变并使其进入能量状态的分子机制。具体而言，我们将1)确定PLCγ1调节B细胞能量的分子机制，2)研究一种新分子如何控制PLCγ及其下游途径调节B细胞能量。这种基于机制的研究将从概念上推进我们对自身抗原调节B细胞能量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认识可能为某些疾病确定新的靶向治疗方法。

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.