REGULATION OF FC GAMMA RECEPTOR SIGNALING BY CD81

CD81 对 FC GAMMA 受体信号传导的调节

• 批准号: 6016863
• 负责人: TONY J FLEMING
• 金额: $ 8.78万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6016863
• 关键词: Arthus phenomenon; CD antigens; anaphylaxis; antibody receptor; biological signal transduction; cytokine; immune complex; immunoglobulin E; laboratory mouse; phagocytosis; protein biosynthesis; receptor coupling; systemic lupus erythematosus

Immune complex-mediated activation of Fc gamma receptors (FcgammaR) on inflammatory cells plays a critical role in the pathogenesis of autoimmune diseases. Fc receptors for IgG (FcgammaRI, FcgammaRIII), IgE (FcepsilonRI) and IgA (FcalphaRI) exhibit a high degree of conservation in signaling including utilization of the same signaling subunits (FcRgamma chains), activation of the same non-receptor tyrosine kinases (NRTK) (syk), and phosphorylation of common downstream substrates (PLCgamma1,cbl, shc). CD81 has been identified as a membrane antigen recognized by antibodies which inhibit FcepsilonRI- and FcgammaRIII- mediated degranulation in mast cells. Since inflammatory cells express both CD81 and FCgammaRs, but not FcepsilonRI, it is reasonable to assume that CD81 could also inhibit FcgammaR- signaling in these cells. The overall objectives of this project are to determine the extent of CD81 inhibition of Fc receptor signaling and the mechanism by which CD81 inhibits FcepsilonRI and FcgammaRIII signaling. Three lines of investigation will be employed to meet these objectives. First, CD81- mediated effects on FcgammaR signaling events such as phagocytosis, cytokine synthesis and degranulation will be examined in normal inflammatory cells and lines. Second, since phosphatases regulate Fc and other antigen receptor signaling, the role of tyrosine phosphatases as effectors of CD81 signaling will be assessed. In addition, CD81- mediated effects on late events of FcR-signaling (ras/MAP kinase, focal adhesion kinase activation) as well as CD81-mediated effects on cell matrix adhesion receptors such as VLA4, will comprise a major part of this line of investigation. Third, further experiments will examine the effect of pretreatment of mice with CD81 antibodies in vivo prior to initiation of IgE- and immune complex-mediated Arthus and anaphylactic reactions. The proposed studies address the extent of CD81 inhibition in FcepsilonRI- and FcgammaR function, its mechanism of action and the potential role of CD81 as an inhibitor of immune complex-mediated activation in vivo, clarification of the role of CD81 in FcgammaR signaling will provide pertinent information as to how FcgammaR activation events are regulated in normal and disease conditions.

免疫复合物介导的Fc-Gamma受体(FcGammaR)激活 炎性细胞在慢性阻塞性肺疾病发病机制中起关键作用 自身免疫性疾病。免疫球蛋白Fc受体(FcGammaRI、FcGammaRIII)、IgE (FcepsilonRI)和IgA(FcalphaRI)表现出高度保守性 在包括利用相同信令子单元的信令中 (FcRGamma链)，激活相同的非受体酪氨酸激酶 (NRTK)(SYK)和常见下游底物的磷酸化 (PLCGamma1，CBL，SHC)。CD81已被鉴定为膜抗原 被抑制FcsilonRI-和FcGammaRIII-的抗体识别- 肥大细胞中介导的脱颗粒。由于炎性细胞表达 CD81和FCGammaRs，但不是FcepsilonRI，合理的是 假设CD81也可以抑制这些细胞中的FcGammaR信号。 该项目的总体目标是确定 CD81对Fc受体信号的抑制作用及其机制 抑制FcepsilonRI和FcGammaRIII信号转导。三行 为达到这些目标，将进行调查。第一，CD81- 对吞噬等FcGammaR信号事件的中介作用， 细胞因子合成和脱颗粒将在正常情况下进行检查 炎性细胞和炎性线条。第二，由于磷酸酶调节Fc 等抗原受体信号转导，酪氨酸磷酸酶的作用 作为CD81信号的效应者，我们将进行评估。此外，CD81- FCR信号转导对晚期事件(ras/MAP激酶，局灶性)的中介作用 黏附激酶激活)以及CD81介导的细胞作用 基质黏附受体，如VLA4，将构成主要部分 这条调查路线。第三，进一步的实验将检验 CD81抗体体内预处理对小鼠免疫功能的影响 免疫球蛋白E和免疫复合体介导的阿尔萨斯与过敏反应的启动 反应。建议的研究涉及CD81抑制的程度 在FcepsilonRI-和FcGammaR功能中，其作用机制和 CD81作为免疫复合体介导的免疫抑制因子的潜在作用 体内激活，阐明CD81在FcGammaR中的作用 信令将提供有关FcGammaR如何 激活事件在正常和疾病条件下都受到调节。