PATHOGENSIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

自身免疫性甲状腺疾病（AITD）影响至少6%的女性，超过10%的老年女性。 我们的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，参与控制免疫反应的机制，如果可能的话，根据疾病的免疫学制定预防或治疗措施。 包括MHC基因和特异性CTLA 4等位基因的遗传因素已被许多研究者证明在诱发Graves病中起作用。已证实Graves病患者的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）表位的应答。我们将通过纯化HLA-DR β 1 *03和DQ α 1 *05分子并研究TSH-R和TPO肽的结合亲和力来研究HLA-DR β 1 *03和DQ α 1 *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DR β 1 *03的特定亚组是否主要与Graves病相关，以及为什么在美国黑人中发现的DR β 1 *03分子与Graves病无关，而在白人中发现的分子与Graves病相关。 我们还将分析TSH-R和TPO表位对DR β 1 *07和DQ α 1 *02的相对结合亲和力，这似乎是保护性因子，理论上可能不结合表位。 我们将评估CTLA 4在患者和对照受试者中与Graves病发展相关的特定等位基因遗传相关的功能。 将通过FACs分析和在刺激的细胞中的静息来研究基因的表达，并且将通过在具有抗原和非特异性T细胞刺激分子的淋巴细胞的体外培养期间使用抗CTLA 4抗体来研究功能。 还将研究在有/无抗CTLA 4的增殖期间IL-2的分泌以及在IL-2撤除后的凋亡作为CTLA 4作用的标志物。 将在T细胞亚群中评价CTLA 4功能。 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.