PLCgammas in B Cell Biology and Autoimmunity

B 细胞生物学和自身免疫中的 PLCgamma

• 批准号: 9326899
• 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/9326899
• 关键词: Antibody Formation; Antigens; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Calcineurin Pathway; Cell Maturation; Cells; Cellular biology; Cessation of life; Clonal Deletion; Data; Diglycerides; Disease; Embryo; Enzymes; Human; Immunologic Deficiency Syndromes; Impairment; Inositol; Knockout Mice; Lipids; MAP2K1 gene; MAP3K7 gene; MAPK8 gene; Maintenance; Mediating; Molecular; Molecular Profiling; Mus; Mutant Strains Mice; Mutation; NFKB Signaling Pathway; PLC gamma1; PLCgamma2; Pathogenesis; Pathway interactions; Patients; Play; Protein Deficiency; Protein Isoforms; Proteins; Ras/Raf; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Reporting; Research; Role; Self Tolerance; Self-control as a personality trait; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Therapeutic Intervention; Up-Regulation; anergy; attenuation; autoreactivity; base; clinically relevant; clinically significant; experimental study; immunoglobulin light chain locus; insight; mouse model; mutant; new therapeutic target; novel; phospholipase C gamma; protein kinase C beta; public health relevance; receptor; receptor-mediated signaling; transcription factor; ubiquitin ligase

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.

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Cγ（PLCγ）是一种对BCR信号传导至关重要的脂质酶，刺激PLC γ可产生甘油二酯（DAG）和1，4，5-三磷酸肌醇（IP 3），分别激活PKC β和Ca 2 +/钙调磷酸酶途径。PLCγ有两种亚型，PLCγ1和PLCγ2。以前，我们报道了PLCγ2介导的PKC β/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PLCγ1缺陷导致早期胚胎死亡，我们产生了条件性PLCγ1敲除小鼠，并发现B细胞特异性PLCγ1缺失损害了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PLCγ1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PLCgγ突变改变了BCR信号传导，并在人类患者中引发免疫缺陷和自身免疫性疾病。因此，PLCγ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PLCγ依赖性途径将BCR信号传导中的微小定量变化转化为B细胞中的定性变化，从而使其进入无反应性状态的分子机制。具体而言，我们将1）确定PLCγ1调节B细胞无反应性的分子机制，2）研究一种新分子如何控制PLCγ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。