REGULATION OF FC GAMMA RECEPTOR SIGNALING BY CD81

免疫复合物介导的Fc γ受体（Fc γ R）活化 炎性细胞在炎症的发病机制中起着关键作用， 自身免疫性疾病 IgG Fc受体（Fc γ RI、Fc γ RIII）、IgE FcepsilonRI）和伊加（FcalphaRI）表现出高度的保守性， 在包括利用相同信令子单元的信令中 （FcR γ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 （PLC γ 1、cbl、shc）。 CD 81已被鉴定为膜抗原 被抑制Fc ε RI-和Fc γ RIII-的抗体识别， 介导肥大细胞的脱粒。 由于炎症细胞表达 CD 81和FC γ R，但不是Fc ε RI， 假设CD 81也可以抑制这些细胞中的Fc γ R信号传导。 本项目的总体目标是确定 CD 81抑制Fc受体信号传导和CD 81抑制Fc受体信号传导的机制 抑制Fc ε RI和Fc γ RIII信号传导。 三行 将进行调查以达到这些目标。 首先，CD 81- 介导的对Fc γ R信号传导事件如吞噬作用的影响， 细胞因子的合成和脱粒将在正常人中进行检查。 炎症细胞和细胞系。 其次，由于磷酸酶调节Fc 和其他抗原受体信号传导，酪氨酸磷酸酶的作用 作为CD 81信号传导的效应物。 此外，CD 81- 对FcR信号传导的晚期事件（ras/MAP激酶，局部 粘附激酶激活）以及CD 81介导的对细胞的作用 基质粘附受体如VLA 4，将构成 这条调查线 第三，进一步的实验将检查 用CD 81抗体在体内预处理小鼠后， 启动IgE和免疫复合物介导的Arthus和过敏性 反应. 拟定研究阐述了CD 81抑制程度 在FcepsilonRI和FcgammaR功能中，其作用机制和 CD 81作为免疫复合物介导的 体内活化，阐明CD 81在Fc γ R 信号传导将提供关于Fc γ R 激活事件在正常和疾病条件下受到调节。

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.