Thyroglobulin Peptide Presentation by HLA-DR in Thyroiditis

HLA-DR 在甲状腺炎中呈现甲状腺球蛋白肽

• 批准号: 7024717
• 负责人: YARON TOMER
• 金额: $ 33.9万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024717
• 关键词: Graves disease; MHC class II antigen; antigen presentation; autoimmune thyroiditis; bioinformatics; clinical research; genetic susceptibility; histocompatibility typing; human subject; immunogenetics; laboratory mouse; mass spectrometry; patient oriented research; protein binding; protein protein interaction; protein structure function; thyroglobulin; thyroiditis; tissue /cell culture

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：自身免疫性甲状腺疾病（AITD）非常普遍。大量的数据表明，遗传因素在AITD的发病机制中起着重要作用。最近，我们和其他人已经证明，精氨酸在HLA-DR 31链（DRp 1-Arg 74）的位置74，在肽结合口袋内的存在，与AITD强烈相关。我们还确定了甲状腺球蛋白（Tg）基因中与AITD相关的错义SNP。这些Tg SNP之一显示与HLA-DR的DR β 1-Arg 74变体相互作用的统计学证据，导致AITD的优势比>10。这些发现表明，HLA-DR口袋变异体和Tg之间的分子相互作用可能是AITD发展的核心。因此，我们假设某些DR口袋变体通过影响抗原呈递细胞（APC）向T细胞呈递Tg肽而引起对AITD的易感性或抗性。我们研究的目的是分析Tg肽和特定HLA-DR口袋变体之间的相互作用赋予AITD易感性或保护AITD的机制，并利用这些知识开发AITD的治疗方法。我们的具体目标是：（1）使用分子建模、生物化学和质谱研究来鉴定和表征与疾病相关的HLA-DR口袋变体（DR 31-Arg 74）结合的hTg肽。(2)在实验性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，测试由Arg 74 + APC结合的hTg肽向T细胞的体内呈递。(3)开发，合成和测试可以阻断EAT发展的改变的肽配体。总之，我们提出了一种新的多学科的方法相结合的生物化学，质谱，细胞培养和体内研究的计算建模实验，解剖hTg肽和HLA-DR之间的相互作用，在诱导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，专业知识来自我们对AITD免疫遗传学的研究。我们已经鉴定了新的遗传变异（例如，DRp 1-Arg 74，CD 40 Kozak SNP）和导致AITD发展的机制。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。这可能有助于开发基于知识的治疗和预防方法，用于自身免疫性甲状腺炎，并可能用于其他具有相似发病机制的自身免疫性疾病。