FC RECEPTOR FUNCTION IN NORMALS AND SLE

正常人和 SLE 中的 FC 受体功能

• 批准号: 2079363
• 负责人: Jane E Salmon
• 金额: $ 16.59万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2079363
• 关键词: alleles; antibody receptor; autoantibody; cell sorting; clone cells; histocompatibility antigens; human subject; immunogenetics; immunoglobulin G; kidney disorder; laboratory mouse; molecular cloning; phagocytic dysfunction; polymerase chain reaction; receptor coupling; receptor expression; site directed mutagenesis; systemic lupus erythematosus; tissue /cell culture

Human Fc receptors (FcgammaR) are now recognized to consist of three families with multiple distinct genes, alternative splicing variants, and allelic forms leading to extensive diversity of structure and function. Recent advances bring into focus three observations pertinent to SLE: 1) FcgammaRIIA is a crucial receptor mediating phagocytic function; 2) activation of FcgammaRIIA is characterized by enhanced binding and phagocytic capacity which is unrelated to changes in quantitative expression; and 3) the LR allele of FcgammaRIIA is the only human FcgammaR which recognizes IgG2 efficiently. In SLE, Fcgamma receptor-specific clearance of IgG-sensitized autologous erythrocytes by the mononuclear phagocytes system is impaired. This defect is dynamic and closely related to both renal and nonrenal disease activity, emphasizing the importance of FcgammaR dysfunction in immune complex deposition and the pathogenesis of SLE. Despite this decrease in FcgammaR-mediated clearance, there is a paradoxical increase in monocyte FcgammaR binding capacity for EA in vitro, without a difference in cell surface expression of any class of FcgammaR. Preliminary data indicate that FcgammaRIIA is a compelling candidate responsible for the FcgammaR dysfunction in SLE. Specific studies of FcgammaRII on monocytes in SLE patients has revealed significantly increased FcgammaRIIA-mediated binding, but markedly decreased FcgammaRIIA- mediated phagocytosis, indicating dissociation of receptor-effector coupling. Based on these observations we hypothesize that 1) abnormal FcgammaRIIA function provides a basis for the disease-related defects and abnormal handling of IgG2 subclass containing immune complexes in SLE, and 2) that alleles of FcgammaRIIA and novel forms of FcgammaRIIA with distinct functional capacities may be of important clinical significance as heritable disease susceptibility factors. Therefore, the specific aims of this proposal are: 1. to understand the basis of activation of FcgammaRIIA, (a) to define the mechanism of the increase in binding by FcgammaRIIA in activated cells (b) to define the mechanism of the induced increase in phagocytic efficiency by FcgammaRIIA; 2. to define the counterbalancing effects leading to the defect in phagocytosis by FcgammaRIIA in SLE; 3. to define the role of FcgammaRIIA alleles in relation to pathogenic IgG2 autoantibodies and renal disease in SLE; 4. to study several unique SLE patients with profound abnormalities in FcgammaRIIA function to define potential novel receptor forms. We will focus on identification of FcgammaRIIA as the target receptor for pathogenesis of immune complex-mediated autoimmune diseases. With this information we will be able to define heritable and acquired components of FcgammaR dysfunction in SLE and modulate receptor function to therapeutic advantage.

人类FC受体（FCGAMMAR）现在被认为由三个组成 具有多个不同基因的家族，替代剪接变体， 和等位基因形式，导致了广泛的结构多样性和 功能。 最近的进步将重点的三个观察结果相关 到SLE：1）fcgammariia是介导吞噬细胞的关键受体 功能; 2）激活fcgammariia的特征是增强 结合和吞噬能力与变化无关 定量表达； 3）fcgammariia的LR等位基因是唯一的 有效识别IgG2的人fcgammar。 在SLE中，FCGAMMA受体特异性的IgG敏化自体的清除率 单核吞噬细胞系统的红细胞受损。 这 缺陷是动态的，与肾脏和肾脏疾病密切相关 活动，强调fcgammar功能障碍在免疫中的重要性 SLE的复杂沉积和发病机理。 尽管有这种减少 在FCGAMMAR介导的间隙中，有矛盾的增加 EA体外EA的单核细胞FCGAMMAR结合能力没有差异 在任何类别的FCGAMMAR的细胞表面表达中。 初步数据 表明fcgammariia是负责的引人注目的候选人 SLE中的FCGAMMAR功能障碍。 Fcgammarii的具体研究 SLE患者的单核细胞已显示出明显增加 Fcgammariia介导的结合，但明显降低了fcgammariia- 介导的吞噬作用，表明受体效应的解离 耦合。 基于这些观察结果，我们假设1）异常fcgammariia 功能为疾病相关缺陷和异常提供了基础 处理含有SLE的免疫复合物的IgG2亚类，2） fcgammariia的等位基因和新型的fcgammariia等位基因 功能能力可能具有重要的临床意义 可遗传的疾病易感性因素。 因此，具体目的 该提议的内容是： 1。了解激活fcgammariia的基础， （a）定义结合增加的机制 活化细胞中的fcgammariia （b）定义诱导的增加的机制 Fcgammariia的吞噬效率； 2。定义平衡效应，导致缺陷 SLE中的Fcgammariia吞噬作用； 3。定义fcgammariia等位基因的作用 SLE中的致病性IgG2自身抗体和肾脏疾病； 4。研究几个独特的SLE患者，异常异常 在fcgammariia功能中，定义了潜在的新型受体形式。 我们将专注于识别fcgammariia作为目标受体 免疫复合物介导的自身免疫性疾病的发病机理。 和 这些信息我们将能够定义可遗传和获得的信息 SLE和调制受体功能中FCGAMMAR功能障碍的成分 为了治疗优势。