PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

自身免疫性甲状腺疾病(Graves病、甲状腺炎、粘液性水肿病) 6%的女性会在一生中受到影响。原因很可能是 涉及抗原异常提呈、异常DR的多因素 表达，以及T细胞抑制电路的异常。我们 假设T细胞免疫甲状腺微粒体抗原是一种 自身免疫性甲状腺疾病的主要因素，我们将分析 仔细研究T细胞和微粒体抗原的相互作用。抗原 将对来自甲状腺组织的特定T细胞克隆进行研究 因为它们有能力控制B细胞特异性抗体的产生， 对甲状腺细胞的细胞毒作用，并诱导 免疫调节反应。一个主要的表位将在 确定T细胞免疫反应性的微粒体抗原-甲状腺过氧化物酶 将细胞克隆到纯化的微粒体抗原、多肽片段和 合成肽。T细胞受体变量Vα和Vβ 片段将被克隆和测序，以确定是否有一个V片段 在形成T细胞受体的基因重排中被看好。独特型的人 针对微粒体T细胞受体的单抗 抗原特异性T细胞克隆将被开发出来。微粒体的释放 来自体外培养的甲状腺细胞的抗原-甲状腺过氧化物酶将被 分析，以努力确定免疫系统是如何暴露在 抗原。这些研究应该确定甲状腺上的表位(S) T细胞识别的微粒体抗原及其特异性反应 将T细胞转化为抗原。如果存在一种显性微粒体抗原 T细胞表位，或有限表位，抗T细胞的单抗 抗原的受体可以使特定的 免疫抑制疗法。 我们对Vα和Bβ基因片段的分析可能定义其用途 在T细胞受体基因重排中的优先片段，因此 找出一个可遗传的因素，它可能在 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.