PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

我们研究计划的目的是了解自身免疫的原因。 甲状腺疾病，免疫反应的机制，如果可能的话， 制定预防性或治疗性免疫调节措施。我们会 确定TSH受体(HTSH-R)的优势表位和致病表位， 确定促进疾病的遗传因素，确定 表位识别与MHG基因分型的关系及其研究潜力 SCID小鼠模型的体内外免疫治疗措施。 将使用重组抗原和人工合成抗原来识别表位 与PBMG、T细胞株及T细胞克隆反应的多肽 GD患者和对照组。我们将研究人口，家庭有一个 高发病率的GD，特别是纯合子的HLA-DQA1*0501患者，以及 这种家庭中的年轻个体处于疾病的早期阶段。至 确定我们将考虑的表位的生物学重要性1) 比较GD患者和对照组的不同反应性，2) PBMC与衍生T细胞系和克隆反应性的一致性，3) 表位识别与疾病和MHC基因的相关性 家族，4)年轻家庭成员的表位识别 有GD风险，5)抗原后淋巴细胞反应性改变 6)特定表位与MHG基因的关系。表位 在多肽发生突变后，将分析其反应性。肽类 它可能能够作为天然表位的拮抗剂，或者 在体外诱导T细胞系或克隆的无能将被研究。我们 将在SCID小鼠身上研究T细胞株对 特定表位，以重建甲状腺炎和产生甲状腺 同种异体异种移植动物的刺激性抗体 甲状腺组织。在这个模型中，我们还可以测试多肽拮抗剂， 表位诱导T细胞无能，抗原诱导耐受。 第二类MHC的基因类型将由特定的聚合酶链式反应/位点决定。 高加索人群、黑人人群、 以及高加索人和黑人家庭群体，以确定人类白细胞抗原与 疾病。因为很明显，人类白细胞抗原的关联只解释了 基因的影响，我们将继续打字，在特定的高度信息量 家族，至少八个候选免疫相关基因组成的一组 与GD的关联。

The aim of our research program is to understand the causes of autoimmune thyroid disease, the mechanism of the immune response and, if possible, to develop preventative or therapeutic immunomodulatory measures. We will identify dominant and pathogenic epitopes of TSH receptor (hTSH-R), determine genetic factors promoting the disease, determine the relationship of epitope recognition to MHG genotypes, and study potential immunotherapeutic measures in vitro and in vivo in a SCID mouse model. Epitopes will be identified using recombinant antigen and synthetic peptides reacting with PBMG, T cell lines and T cell clones derived from patients with GD and controls. We will study populations, families with a high incidence of GD, especially homozygous HLA-DQA1 *0501 patients, and young individuals in such families in the early phase of disease. To establish biologic importance of the epitopes we will consider 1) differential reactivity comparing patients with GD and controls, 2) concordance of reactivity by PBMC, and derived T cell lines and clones, 3) correlation of epitope recognition with disease and MHC genotype within families, 4) recognition of epitopes in young family members genetically at risk for GD, 5) changes in lymphocyte reactivity following antigen deprivation, and 6) relation of specific epitopes to MHG genes. Epitope reactivity will be analyzed following mutation of the peptide. Peptides which may be able to act as antagonists to the natural epitope, or to induce anergy in T cell lines or clones in vitro will be investigated. We will study, in SCID mice, the ability of T cell lines, reacting to specific epitopes, to reconstitute thyroiditis and produce thyroid stimulating antibodies in animals also xeno- transplanted with isologous thyroid tissue. In this model we can also test peptide antagonists, epitope induced T cell anergy, and induction of tolerance by antigen. Class II MHC genotypes will be determined by a PCR/site specific oligonucleotide methodology in Caucasian populations, Black populations, and Caucasian and Black family groups, to determine linkage of HLA with disease. Since it is clear that HLA associations explain only part of the genetic influence, we will proceed to type, in specific highly informative families, a group of at least eight candidate immune-associated genes for linkage to GD.