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

基本信息

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
项目类别：
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

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

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项目摘要

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/摘要重要的数据暗示自身抗体在RA发病机理中对瓜氨酸蛋白的作用，并且在柠檬化酶肽氨基氨酸酶4（PAD4）的自身抗体也在患有最严重关节疾病的患者。柠檬化是肽基 - 依赖钙的转化率精氨酸通过垫酶到瓜氨酸，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。尽管已经提出了不同的几种机制，但我们已发表和初步数据暗示细胞毒性淋巴细胞介导的嗜中性粒细胞在一代中杀死 RA患者的一部分中的柠檬酸硫化自身抗原和免疫原性PAD4。致病作用在此过程中，细胞毒性T淋巴细胞（CTL）得到了我们对T患者的初步工作的强烈支持细胞大颗粒状淋巴细胞白血病（T-LGLL），一种罕见的白血病形式，其中20-30％的患者发展 RA（T-LGLL/RA）。该疾病的特征是CD8+ T细胞，中性粒细胞减少和体细胞的克隆膨胀激活Stat3中的突变。有趣的是，我们发现自身免疫和遗传相似性 T-LGLL/RA和RA的抗PAD4抗体阳性亚组，这表明常见的致病起源这两种疾病中关节炎的发展。重要的是，这些发现使T-LGLL/RA成为强大的由致病性CTL驱动的简化人类模型，其中研究了RA中的新型致病机制。在这个项目，我们将使用独特的RA和T-LGLL/RA患者，以及创新和状态艺术技术是为了研究新的假设，即致病性CTL杀死中性粒细胞是一种中心在独特的血清学不同RA子集中促进对自身抗原的耐受性的机制。到解决这个假设，我们将定义：1）与自动反应性CTL扩展相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了从垂死的中性粒细胞到自动反应性CD4+的自身抗原的曲目 T细胞通过抗原呈递细胞； 3）自动反应性CD8+ T的克隆，特异性和效应子功能 RA和T-LGLL/RA中的细胞。我们的长期目标是运用这些知识来定义指导的精确机制 RA中的预防和治疗干预措施。