PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

描述(申请人提供)：Graves病是一种常见的甲状腺疾病，由自身免疫性疾病引起，可产生严重的并发症，包括心脏问题和眼睛疾病。环境因素起到了一定的作用，但疾病的发展受到遗传因素的强烈制约，包括特定的人类白细胞抗原II类基因的遗传，以及特定版本的CTLA-4基因。我们以前已经研究了第二类MHC基因在Graves病中的作用，它们通过将TSH受体衍生的T细胞表位呈递到抗原提呈细胞上，在T细胞中发挥免疫作用。我们已经证明，某些TSH受体表位经常刺激Graves病患者的T细胞，与HLA-DRbetal*0301具有中等亲和力。我们将研究TSH受体表位、HLA蛋白和T细胞之间的相互作用，以更好地了解疾病的发展和可能抑制免疫过程的方法。TSH受体表位与我们的Graves病患者中常见的所有DR和DQ蛋白的结合将详细说明，并与患者的基因和来自相同基因的患者的T细胞的反应性有关。利用计算机算法、亲和力研究和T细胞反应，以及从DR蛋白洗脱表位测序中获得的信息，我们将建立重要的或免疫主导的TSH受体T细胞表位。有了这些信息，我们将尝试获得突变的TSH受体序列，以抑制患者T细胞对TSH受体表位的反应。我们还将使用结合在DR或DQ分子或四聚体中的TSH受体表位，在体外从患者血液样本中去除反应性T细胞，以确定是否可以找到一种方法来降低免疫反应性。在TSH-R免疫的小鼠的Graves病模型中，我们将开发出可能抑制疾病进程的表位，包括眼病的发展。这样的表位在未来可能同样用于患者。我们的研究将与A.Godkin博士合作完成，他将在计算机算法中分析TSH-R表位，R.G.菲尔普斯博士将分析我们从DR3分子中洗脱出来的TSH-R表位，郭伟民博士将提供DR3四聚体，以及M.Ludgate博士将在Graves病模型上合作。

DESCRIPTION (provided by applicant): Graves' disease is a common disease of the thyroid caused by autoimmunity and can produce serious complications including cardiac problems and eye disease. Environmental factors play some role, but development of disease is strongly conditioned by genetic factors including inheritance of specific HLA Class II genes, and a specific version of the CTLA-4 gene. We have previously investigated the role of Class II MHC genes in Graves' disease through their presentation of T cell epitopes derived from the TSH receptor on antigen presenting cells, to T cells, in the development of immunity. We have shown that certain TSH receptor epitopes, which frequently stimulate T cells from patients with Graves' disease, bind with moderate affinity to HLA-DRbetal*0301. We will study the interaction of TSH receptor epitopes, HLA proteins, and T cells to better understand the development of disease and methods for possible inhibition of the immune process. Binding of TSH receptor epitopes to all of the DR and DQ proteins commonly found in our Graves' patients will be detailed and related to the genotype of the patient and reactivity of T cells from patients with the same genotype. Using computer algorithms, affinity studies, and T cell responses, as well as information gained from sequencing eluted epitopes from DR protein, we will establish the important or immunodominant TSH receptor T cell epitopes. With this information in hand, we will attempt to derive mutated TSH receptor sequences which inhibit the response of patients' T cells to TSH receptor epitopes. We will also use TSH receptor epitopes bound in DR or DQ molecules, or in tetramers, to remove reactive T cells from patient blood samples in vitro to determine whether a method can be found to reduce immunoreactivity. In a model of Graves' disease in TSH-R-immunized mice, we will develop epitopes that may inhibit the disease process, including the development of ophthalmopathy. Such epitopes might similarly be used in patients in the future. Our studies will be done in collaboration with Dr. A. Godkin, who will analyze TSH-R epitopes in a computer algorithm, Dr. R .G. Phelps, who will analyze TSH-R epitopes which we elute from DR3 molecules, Dr. W. Kwok, who will provide DR3 tetramers, and with Dr. M. Ludgate on the model of Graves' disease.