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: 7571614
• 负责人: YARON TOMER
• 金额: $ 38.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571614
• 关键词: Adoptive Transfer; Affinity; Amino Acids; Antigen-Presenting Cells; Arginine; Autoimmune Diseases; Autoimmune thyroiditis; Binding; Biochemical; Bioinformatics; Cathepsins; Cell Culture Techniques; Cells; Charge; Cleaved cell; Complex; Computer Simulation; Data; Development; Disease; Disease susceptibility; Etiology; Exons; Genes; Genetic; Glutamine; Goals; Graves' Disease; HLA-DR Antigens; HLA-DR3 Antigen; Hashimoto Disease; Human; Immunization; Immunogenetics; Knowledge; Lead; Ligands; Mass Spectrum Analysis; Measurement; Modeling; Molecular; Molecular Models; Mus; Odds Ratio; Pathogenesis; Pathogenicity; Patients; Peptide Fragments; Peptides; Play; Positioning Attribute; Predisposition; Prevention approach; Resistance; Role; Single Nucleotide Polymorphism; Splenocyte; T-Cell Receptor; T-Lymphocyte; TNFRSF5 gene; Testing; Thyroglobulin; Thyroiditis; Transgenic Mice; Transgenic Organisms; Variant; autoimmune thyroid disease; base; design; genetic variant; immunogenic; in vivo; knowledge base; molecular modeling; novel; research study; response; therapy development

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.

自身免疫性甲状腺疾病（AITD）非常普遍。大量数据证明了其重要作用 AITD 发病机制中的遗传因素。最近，我们和其他人已经证明，存在 HLA-DR31 链 (DRp1-Arg74) 第 74 位的精氨酸位于肽结合口袋内， 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 SNP 基因。其中一个 Tg SNP 显示了与 HLA-DR(31-Arg74 变体)相互作用的统计证据。 DR，导致 AITD 的优势比>10。这些发现表明，分子之间的相互作用 HLA-DR 口袋变异和 Tg 可能是 AITD 发展的核心。因此，我们假设 某些 DR 口袋变异通过影响 Tg 的呈现而导致对 AITD 的易感性或耐药性 抗原呈递细胞 (APC) 将肽传递给 T 细胞。我们研究的目标是分析 Tg 肽和特定 HLA-DR 口袋变体之间相互作用的机制 对 AITD 的易感性或防御能力，并利用这些知识来开发 AITD 的治疗方法。我们的 具体目标是： (1) 鉴定和表征与 HLA-DR 相关疾病结合的 hTg 肽 使用分子建模、生化和质谱研究进行口袋变体（DR31-Arg74）。 (2) 至 在实验中体内测试 Arg74+ APC 结合的 hTg 肽向 T 细胞的呈递 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， 合成并测试可以阻止 EAT 发展的改变的肽配体。总之，我们建议 一种新颖的多学科方法，将计算建模实验与生化、质量相结合 通过光谱分析、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， 我们从 AITD 免疫遗传学研究中获得了专业知识。我们已经鉴定出新的基因 导致 AITD 发展的变异（例如 DRp1-Arg74、CD40 Kozak SNP）和机制。这 拟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。这可能 促进基于知识的自身免疫治疗和预防方法的发展 甲状腺炎以及可能具有相似发病机制的其他自身免疫性疾病。