Costimulation Genes and Pathways in Multiple Sclerosis

多发性硬化症的共刺激基因和通路

• 批准号: 7871925
• 负责人: David A. Hafler
• 金额: $ 39.65万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871925
• 关键词: ALCAM gene; Address; Affect; Alleles; Autoimmune Diseases; Binding; CD4 Positive T Lymphocytes; CD6 antigen; CTLA4 gene; Cell physiology; Cell surface; Cells; Collaborations; Data; Defect; Disease; Disease Pathway; Drug Delivery Systems; Employee Strikes; Etiology; Exhibits; Functional disorder; Future; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genotype; Grant; Human; IL2RA gene; Immune; Immune response; Immunologics; Immunology; Immunophenotyping; Individual; Inflammation; Inflammatory; Institutes; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-17; Investigation; Lead; Length; Ligand Binding Domain; Ligands; Ligation; Linkage Disequilibrium; Mediating; Memory; Multiple Sclerosis; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Production; Program Research Project Grants; Protein Isoforms; RNA Interference; RNA Splicing; Regulation; Regulatory T-Lymphocyte; Relapsing-Remitting Multiple Sclerosis; Relative (related person); Research; Risk; Role; Scanning; Shapes; Signal Transduction; Small Interfering RNA; Suppressor-Effector T-Lymphocytes; T cell differentiation; T-Cell Activation; T-Lymphocyte; Tissues; Translating; Universities; Variant; base; cell type; cohort; cytokine; disorder risk; genetic variant; genome wide association study; immune function; monocyte; novel therapeutic intervention; prevent; programs; receptor; response; tool

Genome wide association (GWA) scans have allowed an assessment of disease pathways in patients with MS and Tl D based on the unbiased identification of gene variants. We will investigate these allelic variants and their pathways that are both common (CD226/TIGIT) and unique (CTLA4-T1D and CD6-MS) to these diseases. The central role of Thi7 and regulatory T cells in MS has recently been elucidated, and as part of this PPG we demonstrated a loss of regulatory T cell function in MS. We also discovered that increasing the strength of signal through the TCR influences the plasticity of CD4+CD25high Tregs to become Thi7 cells. These data have led to the underlying hypothesis that allelic variants in multiple costimulatory pathways lead to a shift from regulatory to inflammatory T cell function. We will explore the costimulatory pathways identified from GWA scans in relationship to Treg and Thi7 function, investigating the CTLA-4/CD28, CD226/TIGIT, and CD6 pathways. Specifically, we will determine: 1) the role of sCTLA4 in the function and plasticity of human Treg populations in close collaboration with Wicker/Todd; 2) how CD6 MS-risk alleles that induce splice variants alter the CD6 costimulatory pathway, investigating the hypothesis that alterations in the CD6 isoforms affect binding to its ligand results in changes influencing the function of Tri and Tregs in patients with MS; and 3) how the CD226/TIGIT costimulatory pathway modulate Treg and Thi 7 function in human autoimmune disease. Our preliminary data demonstrate a lack of TIGIT expression on Thi7 cells while blocking CD226 corrects defects in Treg function in MS leading us to hypothesize that allelic variants in the CD226/TIGIT pathways influence Th17 and Treg function. We will directly examine whether defects in Treg suppression in MS and hyperactivation of monocytes in patients with T1D are corrected by promoting TIGIT signaling. In summary, it is clear that genetic risk to develop autoimmune disease is due to many common and rare allelic variants each with a small effect that together lead to organ specific inflammation in response to undefined environmental challenges. We will apply new tools to examine how genetic variants lead to the heightened immune responses observed in patients with autoimmune diseases.

全基因组关联（GWA）扫描可以评估患有以下疾病的患者的疾病途径： MS 和 T1 D 基于基因变异的公正鉴定。我们将研究这些疾病的常见（CD226/TIGIT）和独特（CTLA4-T1D 和 CD6-MS）等位基因变异及其途径。最近阐明了 Thi7 和调节性 T 细胞在 MS 中的核心作用，作为该 PPG 的一部分，我们证明了 MS 中调节性 T 细胞功能的丧失。我们还发现，通过 TCR 增加信号强度会影响 CD4+CD25high Tregs 成为 Thi7 细胞的可塑性。 这些数据得出了一个基本假设，即多个共刺激途径中的等位基因变异导致 T 细胞功能从调节性向炎症性 T 细胞功能的转变。我们将探索 GWA 扫描中确定的与 Treg 和 Thi7 功能相关的共刺激通路，研究 CTLA-4/CD28、CD226/TIGIT 和 CD6 通路。具体来说，我们将与 Wicker/Todd 密切合作确定：1) sCTLA4 在人类 Treg 群体功能和可塑性中的作用； 2) 诱导剪接变异的 CD6 MS 风险等位基因如何改变 CD6 共刺激通路，研究 CD6 亚型的改变影响与其配体结合的假设，从而导致影响 MS 患者中 Tri 和 Tregs 功能的变化； 3) CD226/TIGIT 共刺激通路如何调节人类自身免疫性疾病中的 Treg 和 Thi 7 功能。我们的初步数据表明 Thi7 细胞缺乏 TIGIT 表达 而阻断 CD226 可以纠正 MS 中 Treg 功能的缺陷，这使我们推测 CD226/TIGIT 通路中的等位基因变异会影响 Th17 和 Treg 功能。我们将直接检查 MS 中的 Treg 抑制缺陷和 T1D 患者中的单核细胞过度活化是否可以通过促进 TIGIT 信号传导来纠正。总之，很明显，发生自身免疫性疾病的遗传风险是由许多常见和罕见的等位基因变异引起的，每个变异都有很小的影响，这些变异共同导致器官特异性炎症，以应对不确定的环境挑战。我们将应用新工具来研究遗传变异如何导致自身免疫性疾病患者的免疫反应增强。