PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

自身免疫性甲状腺疾病（Graves病、甲状腺炎、粘液水肿） 影响了6%的女性 原因可能是 涉及抗原呈递异常、异常DR的多因素 表达和T细胞抑制电路异常。 我们 假设甲状腺微粒体抗原T细胞免疫是一种 自身免疫性甲状腺疾病的主要因素，我们将分析 仔细观察T细胞与微粒体抗原的相互作用。 抗原 将研究来源于甲状腺组织的特异性T细胞克隆 由于它们控制B细胞特异性抗体产生的能力， 针对甲状腺细胞的细胞毒性， 免疫调节反应。 将在以下中寻找显性表位： 微粒体抗原-甲状腺前氧化酶通过定义T 细胞克隆至纯化的微粒体抗原、肽片段，和 合成肽 T细胞受体可变区V α和V β 片段将被克隆和排序，以确定一个V片段是否 有利于基因重排形成T细胞受体。 独特型 针对微粒体T细胞受体的单克隆抗体 将开发抗原特异性T细胞克隆。 微粒体释放 体外培养的甲状腺细胞的抗原甲状腺过氧化物酶将 分析，以确定免疫系统如何暴露于 抗原。 研究应确定甲状腺上的表位 T细胞识别的微粒体抗原，以及 T细胞与抗原结合 如果存在显性微粒体抗原 表位或有限表位，针对T细胞的单克隆抗体 抗原的受体可以使特异性的 免疫抑制治疗 我们对V α和B β基因片段的分析可能会定义 T细胞受体基因重排中的有利片段， 确定一个遗传因素，这可能是重要的， 这些疾病的发展。

Autoimmune thyroid disease (Graves' disease, thyroiditis, myxedema) affects 6% of women during their life span. The cause is probably multifactorial involving abnormal presentation of antigen, aberrant DR expression, and abnormalities in T cell suppressor circuits. We hypothesize that T cell immunization to thyroid microsomal antigen is a major factor in autoimmune thyroid disease, and we will analyze carefully the interaction of T cells and microsomal antigen. Antigen specific T cell clones derived from thyroid tissue would be investigated for their ability to control B cell specific antibody production, cytotoxicity directed to thyroid cells, and induction of immunoregulatory responses. A dominant epitope will be sought in microsomal antigen-thyroid preoxidase by defining immunoreactivity of T cell clones to purified microsomal antigen, peptide fragments, and synthetic peptides. The T cell receptor variable V alpha and V beta segments will be cloned and sequenced to determine whether one V segment is favored in gene rearrangement forming T cell receptors. An idiotypic monoclonal antibody directed to the T cell receptor of microsomal antigen specific T cell clones will be developed. Release of microsomal antigen-thyroid peroxidase from thyroid cells cultured in vitro will be analyzed, in an effort to determine how the immune system is exposed to the antigen. The studies should define the epitope(s) on thyroid microsomal antigen recognized by T cells, and the specific responses of the T cells to the antigen. If there is a dominant microsomal antigen epitope, or limited epitopes, monoclonal antibodies to the T cell receptor for the antigen could allow development of specific immunosuppressive therapy. Our analysis of the V alpha and B beta gene segments may define the use of favored segments in T cell receptor gene rearrangement, and thus identify a hereditable factor which could be important in the development of these diseases.