PATHOGENSIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

自身免疫性甲状腺疾病(AITD)影响着一生中至少6%的女性，以及超过10%的老年女性。我们研究计划的广泛目标是了解人类自身免疫性甲状腺疾病的原因，控制免疫反应的机制，并在可能的情况下，根据疾病的免疫学制定预防或治疗措施。遗传因素，包括MHC基因的遗传和特定的CTLA4等位基因，已被许多研究人员证明在Graves病的易感性中起作用。在Graves病患者中，T细胞、T细胞系和T细胞克隆对特异性TSH受体(TSH-R)和甲状腺过氧化物酶(TPO)表位的反应已被证明。我们将通过纯化这些分子并研究TSH-R和TPO多肽的亲和力来研究人类白细胞抗原-DRbeta1*03和DQalpha1*05与Graves病相关的机制。我们将询问结合亲和力是否与表位刺激T细胞的能力相对应。我们还将确定DRbeta1*03的特定亚群是否主要与Graves病有关，以及为什么在美国黑人中发现的DRbeta1*03分子与Graves病无关，而在高加索人中发现的分子与Graves病有关。我们还将分析TSH-R和TPO表位与DRbeta1*07和DQalpha1*02的相对结合亲和力，这似乎是保护因子，理论上可能不结合表位。我们将评估CTLA4在患者和对照受试者中与Graves病发生相关的特定等位基因遗传的关系。该基因的表达将通过FACS分析和在刺激细胞中休息来研究，并将在含有抗原和非特异性T细胞刺激分子的淋巴细胞的体外培养过程中使用抗CTLA4抗体来研究其功能。在有或没有抗CTLA4的情况下，增殖过程中IL-2的分泌，以及IL-2退出后的凋亡，也将作为CTLA4作用的标志进行研究。CTLA4功能将在T细胞亚群中进行评估。计划中的研究与人类AITD的发展有直接关系，也适用于其他自身免疫性疾病，如糖尿病。

Autoimmune thyroid disease (AITD) affects at least 6 percent of all women in their lifetime, and more than 10 percent of older women. The broad aim of our research program is to understand the causes of human autoimmune thyroid disease, the mechanisms involved in controlling the immune response, and, if possible, to develop preventive or therapeutic measures based on the immunology of the disease. Genetic factors including inheritance of MHC genes and specific CTLA4 alleles have been shown by many investigators to play a role in predisposing to Graves' disease. Responses to specific TSH receptor (TSH-R), and thyroid peroxidase (TPO) epitopes, have been demonstrated for T cells, T cell lines, and T cell clones in patients with Graves' disease. We will study the mechanism through which HLA-DRbeta1*03 and DQalpha1*05 are associated with Graves' disease, by purifying these molecules and studying the affinity of TSH-R and TPO peptides for binding. We will ask whether the binding affinity corresponds with the ability of the epitopes to stimulate T cells. We will also determine whether specific subgroups of DRbeta1*03 are primarily associated with Graves' disease, and why the DRbeta1*03 molecule found in Black Americans is not associated with Graves' disease, while the molecule found in Caucasians is associated with Graves' disease. We will also analyze the relative binding affinity of TSH-R and TPO epitopes for DRbeta1*07 and DQalpha1*02, which appear to be protective factors and, in theory, might not bind the epitopes. We will assess the function of CTLA4 in patients and control subjects in relation to inheritance of a specific allele associated with development of Graves' disease. Expression of the gene will be studied by FACs analysis and resting in stimulated cells, and function will be studied by use of anti-CTLA4 antibodies during in vitro culture of lymphocytes with antigen and nonspecific T cell stimulating molecules. Secretion of IL-2 during proliferation with/without anti-CTLA4, and apoptosis after withdrawal of IL-2, will also be studied as markers for CTLA4 action. CTLA4 function will be evaluated in T cell subsets. The studies planned have direct bearing on development of AITD in humans, and also apply to other autoimmune disease such as Diabetes.