IMMUNOPATHOLOGY OF B-CELL AND NEURONAL AUTOANTIGENS

生物合成酶的较小形式， 神经递质GABA，谷氨酸脱羧酶（GAD 65）， 在中枢神经系统的GABA能神经元中， 胰腺β-细胞。这种蛋白质是两种主要的自身抗原 影响其表达位点的人类疾病，胰岛素依赖性 糖尿病（IDDM），这是由于自身免疫性破坏 和僵硬人综合征（SMS），一种罕见的神经系统疾病， 由GABA能神经元功能障碍引起的疾病。虽然 SMS患者中IDDM的符合率高， 发展SMS。要检验的主要假设是：i）SMS是由 通过针对GAD 65中不同表位的自身抗体ii）IDDM是由 通过GAD 65特异性细胞毒性T细胞破坏β-细胞，和iii） B细胞在胰岛素依赖型糖尿病中起抗原呈递细胞的作用。整体 这里提出的工作目标是了解分子 GAD 65的自身免疫机制及其在各种疾病中的作用。 第一个和第二个目的提出表征人B细胞， GAD 65中的T细胞表位及其与每种疾病和 人类的HLA易感性和保护性单倍型。更大的形式 GAD 67与GAD 65高度同源，但 在两种疾病中不起自身抗原的作用，提供了一种 重要的参考分子。第三个目的是研究 动物模型中自身免疫和对GAD 65耐受的机制。 如果对GAD 65的自身免疫是这两种疾病的病因， 将是重要的抗原特异性免疫方法的发展， 预防如果对GAD 65的自身免疫不是致病性的，而是一种 疾病发展的标志物，结果对诊断很重要 和预测在每种疾病和耐受机制， 对外周抗原的自身免疫。

The smaller form of the biosynthesizing enzyme for the inhibitory neurotransmitter GABA, glutamic acid decarboxylase (GAD65), is expressed at comparable levels in GABA-ergic neurons in the central nervous system and in pancreatic (3-cells. This protein is a major autoantigen in two human diseases that affect its sites of expression, insulin dependent diabetes mellitus (IDDM), which results from an autoimmune destruction of the (3-cell, and stiff-man syndrome (SMS), a rare neurological disorder caused by a dysfunction of GABA-ergic neurons. Although there is a high coincidence of IDDM in SMS patients, very few IDDM patients develop SMS. The major hypothesis to be tested are i) that SMS is caused by autoantibodies to a distinct epitope in GAD65 ii) that IDDM is caused by GAD65 specific cytotoxic T-cells which destroy the (3-cell, and iii) that B-cells play a role as antigen presenting cells in IDDM. The overall objective of the work proposed here is to understand the molecular mechanisms of autoimmunity to GAD65 and its role in each disease. The first and second aims propose to characterize the human B-cell and T-cell epitopes in GAD65 and their correlation with each disease and with HLA-susceptibility and protective haplotypes in humans. The larger form of the enzyme, GAD67, which is highly homologous to GAD65 and yet does not play a role as an autoantigen in either disease, provides an important reference molecule for those studies. The third aim is to study mechanisms of autoimmunity and tolerance to GAD65 in animal models. If autoimmunity to GAD65 is causative for either disease, the results will be important for development of antigen specific methods of immuno prevention. If autoimmunity to GAD65 is not pathogenic but rather a marker of disease development, the results are important for diagnosis and prediction in each disease and for mechanisms of tolerance and autoimmunity to peripheral antigens.