Thyroglobulin Peptide Presentation by HLA-DR in Thyroiditis

自身免疫性甲状腺疾病(AITD)非常普遍。大量数据表明， 遗传因素在AITD发病机制中的作用最近，我们和其他人已经证明了 位于人类白细胞抗原-DR31链第74位的精氨酸(Drp1-Arg74)位于多肽结合口袋内。 与AITD密切相关。我们还在甲状腺球蛋白(TG)中发现了与AITD相关的错义SNPs。 吉恩。其中一个TG SNPs显示了与DR(31-Arg74变种的人类白细胞抗原)相互作用的统计证据。 DR，导致AITD的优势比为10。这些发现表明，分子间的相互作用 HLA-DR口袋变异体和TG可能在AITD的发生发展中起中心作用。因此，我们假设 某些DR口袋变异体通过影响TG的呈现而导致对AITD的易感性或耐药性 通过抗原提呈细胞(APC‘s)将多肽转化为T细胞。我们研究的目标是分析 TG多肽与特定的人类白细胞抗原DR口袋变异体相互作用的机制 对AITD的易感性或对AITD的保护，并利用这些知识开发AITD的治疗方法。我们的 具体目标是：(1)鉴定与疾病相关的人类白细胞抗原-DR结合的hTG多肽 口袋变异体(DR31-Arg74)，使用分子建模、生化和质谱学研究。(2)至 Arg74 APC结合的HTG多肽呈递给T细胞的体内实验 自身免疫性甲状腺炎(EAT)模型(DR3转基因小鼠)和AITD患者。(3)发展， 合成并测试可阻断EAT发展的改变的多肽配体。综上所述，我们建议 一种计算模拟实验与生化、质量相结合的多学科新方法 光谱分析、细胞培养和体内研究分析HTG多肽与人类白细胞抗原DR的相互作用 在诱发自身免疫性甲状腺炎中起重要作用。我们有能力和专业知识来实现这些目标， 从我们对AITD免疫遗传学的研究中获得的专业知识。我们已经发现了新的基因 突变(例如，Drp1-Arg74、CD40 Kozak SNP)和导致AITD发生的机制。这个 建议的研究将有助于更好地了解自身免疫性甲状腺炎的基本病因学。今年5月 促进发展以知识为基础的自身免疫治疗和预防方法 甲状腺炎，也可能是具有相似致病机制的其他自身免疫性疾病。

Autoimmune thyroid diseases (AITD) are highly prevalent. Abundant data demonstrate a major role for genetic factors in the pathogenesis of AITD. Recently, we and others have demonstrated that the presence of arginine at position 74 of the HLA-DR31 chain (DRp1-Arg74), within the peptide binding pocket, was strongly associated with AITD. We also identified AITD-associated missense SNPs in the thyroglobulin (Tg) gene. One of those Tg SNPs showed statistical evidence for interaction with the DR(31-Arg74 variant of HLA- DR, resulting in an odds ratio of>10 for AITD. These findings suggest that molecular interactions between HLA-DR pocket variants and Tg may be central to the development of AITD. Thus, we hypothesize that certain DR pocket variants cause susceptibility or resistance to AITD by influencing the presentation of Tg peptides to T cells by antigen presenting cells (APC's). The goals of our studies are to analyze the mechanisms by which interactions between Tg peptides and specific HLA-DR pocket variants confer susceptibility to, or protection from, AITD, and to use this knowledge to develop therapies for AITD. Our specific aims are: (1) To identify and characterize hTg peptides that bind to the disease associated HLA-DR pocket variant (DR31-Arg74) using molecular modeling, biochemical, and mass spectrometry studies. (2) To test in-vivo the presentation of hTg peptides bound by Arg74+ APC's to T-cells in an experimental autoimmune thyroiditis (EAT) model (in DR3 transgenic mice), and in AITD patients. (3) To develop, synthesize, and test altered peptide ligands that can block the development of EAT.In summary, we propose a novel multi-disciplinary approach combining computational modeling experiments with biochemical, mass spectrometry, cell culture, and in-vivo studies to dissect the interactions between hTg peptides and HLA-DR in the induction of autoimmune thyroiditis. We have the capacity and expertise to achieve these goals, expertise gained from our studies on the immunogenetics of AITD. We have already identified novel genetic variants in (e.g., DRp1-Arg74, CD40 Kozak SNP) and mechanisms leading to the development of AITD. The proposed studies will lead to a better understanding of the basic etiology of autoimmune thyroiditis. This may facilitate the development of knowledge-based treatment and prevention approaches for autoimmune thyroiditis and possibly for other autoimmune diseases that share similar pathogenetic mechanisms.