IMMUNOPATHOLOGY OF B-CELL AND NEURONAL AUTOANTIGENS

用于抑制的生物合成酶的较小形式 神经递质GABA，谷氨酸脱羧酶(GAD65)表达 中枢神经系统中GABA能神经元的类似水平 胰腺(3-细胞)。这种蛋白质是两种主要的自身抗原 影响其表达部位的人类疾病，依赖于胰岛素 糖尿病(IDDM)，由自身免疫破坏引起 (3-细胞僵人综合征(SMS)，一种罕见的神经学疾病 由GABA能神经元功能障碍引起的疾病。尽管在那里 IDDM在短信患者中的符合率很高，IDDM患者很少 发展短信业务。要检验的主要假设是：i)短信是由 通过针对GAD65中不同表位的自身抗体II)，IDDM是由 由GAD65特异性细胞毒性T细胞破坏(3-细胞，和III) B细胞在IDDM中起抗原提呈细胞的作用。整体而言 这里提出的工作的目的是了解分子 GAD65自身免疫的机制及其在每种疾病中的作用。 第一个和第二个目标建议描述人类B细胞和 GAD65的T细胞表位及其与各种疾病的相关性 人类的HL A易感性和保护性单倍型。较大的表格 GAD67，它与GAD65高度同源，但 在任何一种疾病中都不作为自身抗原发挥作用，提供了一种 这些研究的重要参考分子。第三个目标是研究 动物模型对GAD65自身免疫和耐受机制的研究。 如果对GAD65的自身免疫是导致任何一种疾病的原因，结果是 对抗原特异性免疫方法的发展具有重要意义 预防。如果对GAD65的自身免疫不是致病的，而是一种 疾病发展的标志物，结果对诊断很重要 以及对每种疾病的预测和耐受机制 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.