The role of cytotoxic T cells in rheumatoid arthritis pathogenesis

细胞毒性T细胞在类风湿性关节炎发病机制中的作用

• 批准号: 10689752
• 负责人: Felipe Andrade
• 金额: $ 58.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689752
• 关键词: Address; Alleles; Antibodies; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Arthritis; Autoantibodies; Autoantigens; Autoimmune; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Calcium; Cells; Cessation of life; Citrulline; Clonal Expansion; Clonality; Clone Cells; Complex; Cytolysis; Cytoplasmic Granules; Cytotoxic T-Lymphocytes; DNA Sequence Alteration; Data; Dendritic Cells; Development; Disease; Enzymes; Epitopes; Etiology; Generations; Genetic; Goals; Granzyme; HLA-DRB1; Human; Immune Targeting; Immune response; Inflammation; Isoenzymes; Joints; Killer Cells; Knowledge; Laboratories; Link; Lymphocyte; Maintenance; Mediating; Methods; Modeling; Mutation; Natural Killer Cells; Neutropenia; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Process; Protein-arginine deiminase; Proteins; Publishing; Rheumatoid Arthritis; Role; Series; Serology; Shapes; Specificity; Stat3 protein; Subgroup; T-Cell Large Granular Lymphocyte; Technology; Testing; Therapeutic Intervention; Universities; Virginia; Work; antigen processing; arthropathies; autoreactivity; chronic T-cell leukemia; citrullinated protein; cohort; cytotoxic; cytotoxic CD8 T cells; human model; immunogenic; innovation; insight; leukemia; monocyte; neutrophil; novel; novel therapeutic intervention; patient subsets; perforin; preventive intervention

PROJECT SUMMARY/ABSTRACT Significant data implicate a role for autoantibodies to citrullinated proteins in RA pathogenesis, and autoantibodies to the citrullinating enzyme peptidylarginine deiminase 4 (PAD4) are also found in a subset of patients with the most severe joint disease. Citrullination is the calcium-dependent conversion of peptidyl- arginine to citrulline by the PAD enzymes, but the mechanisms that initiate immune responses to citrullination- associated autoantigens are poorly understood. While different several mechanisms have been proposed, our published and preliminary data implicate cytotoxic lymphocyte-mediated killing of neutrophils in the generation of citrullinated autoantigens and immunogenic PAD4 in a subset of patients with RA. A pathogenic role for cytotoxic T lymphocytes (CTLs) in this process is strongly supported by our preliminary work on patients with T cell large granular lymphocyte leukemia (T-LGLL), a rare form of leukemia in which 20-30% of patients develop RA (T-LGLL/RA). This disease is characterized by clonal expansion of CD8+ T cells, neutropenia and somatic activating mutations in STAT3. Interestingly, we have found striking autoimmune and genetic similarities between T-LGLL/RA and the anti-PAD4 antibody positive subgroup of RA, suggesting a common pathogenic origin for the development of arthritis in these two diseases. Importantly, these findings make T-LGLL/RA a powerful yet simplified human model driven by pathogenic CTLs, in which to study novel pathogenic mechanisms in RA. In this project, we will use unique cohorts of patients with RA and T-LGLL/RA, as well as innovative and state of the art technologies, to examine the novel hypothesis that killing of neutrophils by pathogenic CTLs is a central mechanism promoting the lack of tolerance to autoantigens in a unique serologically distinct RA subset. To address this hypothesis we will define: 1) common pathogenic mechanisms linked to autoreactive CTL expansion and serological profiles indicative of CTL-driven disease in RA and T-LGLL/RA; 2) how the cytotoxic lymphocyte granule pathway shapes the repertoire of autoantigens presented from dying neutrophils to autoreactive CD4+ T cells by antigen presenting cells; and 3) the clonality, specificity and effector functions of autoreactive CD8+ T cells in RA and T-LGLL/RA. Our long-term goal is to apply this knowledge to define precise mechanism-guided preventive and therapeutic interventions in RA.

项目摘要/摘要 重要数据表明瓜氨酸化蛋白自身抗体在RA发病机制中的作用， 瓜氨酸化酶肽基精氨酸脱亚胺酶4（PAD 4）的自身抗体也存在于 患有最严重关节疾病的患者。瓜氨酸是钙依赖性的肽基- 但是，启动对瓜氨酸的免疫应答的机制， 相关的自身抗原知之甚少。虽然已经提出了几种不同的机制，但我们的 已发表的和初步的数据表明，在新生儿中，细胞毒性淋巴细胞介导的嗜中性粒细胞杀伤 瓜氨酸化自身抗原和免疫原性PAD 4在RA患者亚群中的表达。致病作用， 细胞毒性T淋巴细胞（CTL）在这一过程中的作用得到了我们对T淋巴细胞白血病患者的初步研究的有力支持。 细胞大颗粒淋巴细胞白血病（T-LGLL），一种罕见的白血病，20-30%的患者发生 RA（T-LGLL/RA）。这种疾病的特征在于CD 8 + T细胞的克隆性扩增、中性粒细胞减少症和体细胞免疫缺陷。 激活STAT 3突变。有趣的是，我们已经发现了惊人的自身免疫和遗传相似性之间 T-LGLL/RA和RA的抗PAD 4抗体阳性亚群，提示T-LGLL/RA和RA的共同致病源。 这两种疾病的关节炎的发展。重要的是，这些发现使T-LGLL/RA成为一种强大的， 简化的人类模型，由致病性CTL驱动，在其中研究RA的新致病机制。在 在这个项目中，我们将使用独特的RA和T-LGLL/RA患者队列，以及创新和状态， 本领域的技术，以检查新的假设，即致病性CTL杀死中性粒细胞是一个核心的免疫抑制因子。 机制促进缺乏耐受性的自身抗原在一个独特的血清学不同的RA子集。到 针对这一假设，我们将定义：1）与自身反应性CTL扩增相关的常见致病机制 和血清学谱指示RA和T-LGLL/RA中CTL驱动的疾病; 2）细胞毒性淋巴细胞如何在RA中表达， 颗粒途径塑造了从垂死的中性粒细胞呈递到自身反应性CD 4+的自身抗原库 自身反应性CD 8 + T细胞的克隆性、特异性和效应功能 RA和T-LGLL/RA中的细胞。我们的长期目标是应用这些知识来定义精确的机制指导 预防和治疗类风湿关节炎。