Molecular Mechanisms Of Autoimmune Disease

我们研究自身免疫性疾病的细胞和分子基础有两个目的。首先，我们想要确定导致自身免疫性疾病的T细胞的致病作用和抗原特异性，如多发性硬化症、重症肌无力、胰岛素依赖型糖尿病等。其次，我们想要确定诱导细胞凋亡的特异性抗原作为治疗此类自身免疫性疾病的一种手段的可行性。为此，我们在以下几个方面取得了进展：1)我们鉴定了一种对乙酰胆碱受体多肽有强大反应的转基因重症肌无力小鼠模型；在该模型中，我们证实了转基因编码的T细胞受体链的作用主题表达对B淋巴细胞具有毒性作用。2)我们正在研究一组与自身免疫相关的凋亡相关基因，以确定自身免疫的遗传决定因素；以及3)我们正在启动抗原特异性治疗的研究，以防止血友病患者在注射因子VIII后形成封闭抗体。我们还将启动一种新的自身免疫性甲状腺炎转基因小鼠模型的研究。作为这些研究的一部分，我们还试图了解T细胞受体刺激对抗原诱导死亡的调节。这些研究应该会对自身免疫性疾病的发病机制和治疗产生重要的新见解，这种疾病在美国是一个普遍的健康问题，特别是在职业女性中。

We are studying the cellular and molecular basis of autoimmune diseases with two purposes. First, we want to establish the pathogenic role and antigen-specificity of T cells that cause autoimmune diseases such as multiple sclerosis, myasthenia gravis, insulin-dependent diabetes, among others. Second, we would like to determine the feasibility of specific antigen-of ainduced apoptosis as a means of treating such autoimmune diseases. To these ends, we have made progress in the following areas: 1) we have characterized a transgenic T cell receptor mouse model of myasthenia gravis which has a powerful response to a peptide from the acetylcholine receptor; In this model, we have established that act topic expression of the T-cell receptor chains encoded by the transgene have a toxic effect on B lymphocytes. 2) we are studying sets of apoptosis-related genes for association with autoimmunity to establish genetic determinants of autoimmunity; and 3) we are initiating studies of antigen-specific therapy to prevent the formation of blocking antibodies following factor VIII administration to hemophiliacs. We will also be initiating studies of a new transgenic mouse model for autoimmune thyroiditis. As part of these studies we are also trying to understand the regulation of antigen-induced death by T cell receptor stimulation. These studies should yield important new insights into the pathogenesis and treatment of autoimmune diseases which is a widespread health problem in the U.S. particularly among working women.