PLCgammas in B Cell Biology and Autoimmunity

B 细胞生物学和自身免疫中的 PLCgamma

• 批准号: 8825598
• 负责人: DEMIN WANG
• 金额: $ 47.6万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825598
• 关键词: 1,2-diacylglycerol; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Calcineurin Pathway; Cell Maturation; Cellular biology; Cessation of life; Clonal Deletion; Data; Diglycerides; Disease; Embryo; Enzymes; Human; Immunologic Deficiency Syndromes; Inositol; Knockout Mice; Lipids; MAP3K7 gene; Maintenance; Mediating; Molecular; Mus; Mutation; NFKB Signaling Pathway; Pathogenesis; Pathway interactions; Patients; Phospholipase; Play; Protein Isoforms; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Reporting; Research; Role; Self Tolerance; Signal Transduction; anergy; base; clinically relevant; immunoglobulin light chain locus; insight; new therapeutic target; novel; public health relevance; receptor

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 Cg (PLCg), a lipid enzyme critical for BCR signaling, generates diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) that activate the PKCb and Ca2+/ calcineurin pathways, respectively. PLCg has two isoforms, PLCg1 and PLCg2. Previously, we reported a key role for the PLCg2-mediated PKCb/Bcl10/TAK1/IKK/NF-kB signaling pathway in B cell maturation and activation, immunoglobulin light chain locus activation, and BCR receptor editing. As PLCg1 deficiency causes early embryonic death, we generated conditional PLCg1 knockout mice, and discovered that B cell-specific deletion of PLCg1 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 PLCg1 in the establishment of self-tolerance. The clinical relevance of these findings is that PLCg2 mutations alter BCR signaling and elicit immunodeficiency and autoimmune diseases in human patients. Thus, the PLCg 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 PLCg-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 PLCg1 regulates B cell anergy, and 2) study how a novel molecule controls PLCg 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.

描述（由申请方提供）：由B细胞受体（BCR）转导的信号通过控制克隆缺失、受体编辑和无反应性来调节B细胞对自身抗原的耐受性。介导B细胞耐受性的BCR信号尚未完全了解，而引起B细胞耐受性破坏和随之发生的自身免疫性疾病的改变的BCR信号传导更是知之甚少。磷脂酶Cg（PLCg）（一种对BCR信号传导至关重要的脂质酶）的刺激产生二酰基甘油（DAG）和肌醇1，4，5-三磷酸（IP 3），其分别激活PKCb和Ca 2 +/钙调磷酸酶途径。PLCg有两种亚型，PLCg 1和PLCg 2。以前，我们报道了PLC g2介导的PKC B b/Bcl 10/TAK 1/IKK/NF-κ B信号通路在B细胞成熟和活化、免疫球蛋白轻链位点活化和BCR受体编辑中的关键作用。由于PLCg 1缺陷导致早期胚胎死亡，我们产生了条件性PLCg 1敲除小鼠，并发现B细胞特异性缺失PLCg 1损害BCR信号传导，并排除了这些小鼠中B细胞无反应性的维持。这些新数据揭示了PLCg 1在建立自身耐受性中的关键但未被充分认识的作用。这些发现的临床相关性在于PLCg 2突变改变BCR信号传导并引起人类患者的免疫缺陷和自身免疫性疾病。因此，PLCg途径在控制小鼠和人的B细胞耐受性中起重要作用。该更新申请的主要目的是研究PLC g依赖性途径将BCR信号传导中的小的定量变化转化为B细胞中的定性变化的分子机制，所述定性变化驱使它们进入无反应性状态。具体而言，我们将1）确定PLC g 1调节B细胞无反应性的分子机制，2）研究一种新的分子如何控制PLC g及其下游途径来调节B细胞无反应性。这种机制为基础的研究将概念性地推进我们对自身抗原调节B细胞无能的分子信号传导机制的理解。对人类自身免疫性疾病分子发病机制的新认识可能会为某些疾病确定新的靶向治疗方法。