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， AITD发病机制中的遗传因素。最近，我们和其他人已经证明， 在肽结合口袋内的HLA-DR 31链（DRp 1-Arg 74）的位置74处的精氨酸， 与AITD密切相关。我们还在甲状腺球蛋白（Tg）中发现了AITD相关的错义SNP。 基因其中一个Tg SNP显示了与DR（HLA-31-Arg 74变体）相互作用的统计学证据。 DR，导致AITD的优势比>10。这些发现表明， HLA-DR口袋变体和Tg可能是AITD发展的核心。因此，我们假设， 某些DR口袋变体通过影响Tg的呈现而引起对AITD的易感性或抗性 通过抗原呈递细胞（APC）将肽递送至T细胞。我们研究的目的是分析 Tg肽和特异性HLA-DR口袋变体之间的相互作用赋予 对AITD的易感性或保护，并利用这些知识来开发AITD的治疗方法。我们 具体目标是：（1）鉴定和表征与疾病相关的HLA-DR结合的hTg肽 口袋变体（DR 31-Arg 74）的分子建模，生物化学和质谱研究。(2)到 在实验中体内测试Arg 74 + APC结合的hTg肽对T细胞的呈递 自身免疫性甲状腺炎（EAT）模型（在DR 3转基因小鼠中）和AITD患者中。(3)为了发展， 合成，并测试改变肽配体，可以阻止EAT的发展。总之，我们建议， 一种新的多学科方法，将计算建模实验与生物化学、质量 光谱法、细胞培养和体内研究来剖析hTg肽和HLA-DR之间的相互作用 诱发自身免疫性甲状腺炎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 变体（例如，DRp 1-Arg 74，CD 40 Kozak SNP）和导致AITD发展的机制。的 建议的研究将导致更好地了解自身免疫性甲状腺炎的基本病因。这可能 促进发展以知识为基础的治疗和预防方法， 甲状腺炎和可能的其他自身免疫性疾病，共享类似的发病机制。

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.