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: 10276979
• 负责人: Erika Darrah
• 金额: $ 60.85万
• 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/10276979
• 关键词: Address; Alleles; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Arthritis; Autoantibodies; Autoantigens; Autoimmune; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Calcium; Cessation of life; Citrulline; Cleaved cell; 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; Lead; 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; enzyme mechanism; 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 大量数据表明，抗瓜氨酸蛋白自身抗体在类风湿关节炎发病机制中起作用。 瓜氨酸氨基精氨酸脱亚胺酶4(PAD4)的自身抗体也存在于 患有最严重关节疾病的患者。瓜氨酸化是一种依赖钙离子的多肽- 精氨酸通过PAD酶转化为瓜氨酸，但启动对瓜氨酸的免疫反应的机制- 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，细胞毒性淋巴细胞介导的中性粒细胞在世代中的杀伤 瓜氨酸自身抗原和免疫原性PAD4在RA患者中的亚群。一个致病的角色 在这一过程中的细胞毒性T淋巴细胞(CTL)得到了我们对T细胞患者的初步研究的有力支持 细胞性大颗粒淋巴细胞白血病(T-LGLL)，是一种罕见的白血病形式，20%-30%的患者发生在这种白血病中 RA(T-LGLL/RA)。本病的特点是CD8+T细胞克隆性增殖、中性粒细胞减少和体细胞 激活STAT3中的突变。有趣的是，我们发现了惊人的自身免疫和遗传相似性 T-LGLL/RA和抗PAD4抗体阳性的RA亚群之间存在共同的致病机制 关节炎在这两种疾病中的发展。重要的是，这些发现使T-LGLL/RA成为一种强大的 简化致病CTL驱动的人体模型，研究RA的新致病机制。在……里面 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 ART技术，以检验新的假设，即致病CTL杀死中性粒细胞是一个中心 在独特的血清学上不同的RA亚群中促进对自身抗原缺乏耐受性的机制。至 针对这一假设，我们将定义：1)与自身反应性CTL扩增有关的常见致病机制 以及指示RA和T-LGLL/RA中CTL驱动疾病的血清学特征；2)细胞毒性淋巴细胞如何 颗粒途径塑造从垂死的中性粒细胞到自身反应性CD4+的自身抗原库 3)自身反应性CD8+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械制导 类风湿关节炎的预防和治疗干预。