Loss of B cell tolerance in rheumatoid arthritis

类风湿性关节炎 B 细胞耐受性丧失

• 批准号: 8091761
• 负责人: Eric Meffre
• 金额: $ 19.23万
• 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: 2010-08-30 至 2011-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091761
• 关键词: Accounting; Amino Acids; Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Bone Marrow; Characteristics; Clinical; Complementarity Determining Region III; Defect; Development; Disease; Emigrant; Ensure; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Recombination; Goals; Human; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Joints; Mediating; Molecular; Molecular Profiling; Monoclonal Antibody CD20; Mus; Mutate; Onset of illness; Pathogenesis; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Physiology; Process; Production; RNA; Receptor Signaling; Receptors, Antigen, B-Cell; Recombinant Antibody; Recruitment Activity; Reporting; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Rheumatoid Factor; Role; Serum; Shapes; Specificity; Subgroup; Synovial Membrane; Systemic Lupus Erythematosus; Testing; V(D)J Recombination; Work; anergy; autoreactive B cell; base; complementarity-determining region 3; cyclic citrullinated peptide; high risk; kappa-Chain Immunoglobulins; programs; receptor; Accounting; Amino Acids; Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Bone Marrow; Characteristics; Clinical; Complementarity Determining Region III; Defect; Development; Disease; Emigrant; Ensure; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Recombination; Goals; Human; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Joints; Mediating; Molecular; Molecular Profiling; Monoclonal Antibody CD20; Mus; Mutate; Onset of illness; Pathogenesis; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Physiology; Process; Production; RNA; Receptor Signaling; Receptors, Antigen, B-Cell; Recombinant Antibody; Recruitment Activity; Reporting; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Rheumatoid Factor; Role; Serum; Shapes; Specificity; Subgroup; Synovial Membrane; Systemic Lupus Erythematosus; Testing; V(D)J Recombination; Work; anergy; autoreactive B cell; base; complementarity-determining region 3; cyclic citrullinated peptide; high risk; kappa-Chain Immunoglobulins; programs; receptor

DESCRIPTION (provided by applicant): Autoantibodies are a characteristic of most autoimmune diseases including rheumatoid arthritis (RA) and appear in the serum many years before the onset of clinical disease, suggesting an early break in B cell tolerance in RA. An important role for B cells in RA has been supported by successful treatment of RA patients with anti-CD20 monoclonal antibodies that eliminate B cells. The underlying mechanisms that account for autoreactive B cell and autoantibody production in RA are poorly defined. We recently analyzed B cell tolerance in untreated active RA patients by testing the specificity of recombinant antibodies cloned from single new emigrant and mature naive B cells. RA patients exhibit defective central and peripheral B cell tolerance checkpoints that result in the accumulation of serf-reactive mature naive B cells, likely contributing to RA pathogenesis. In addition, about half of RA patients showed new emigrant B cells with defective receptor editing, one of the 3 mechanisms that normally ensure B cell tolerance. The other half of the patients displayed new emigrant B cells with unusually long (11 or more amino acids) complementarity determining region 3 (CDRSs) associated to self-reactivity and found enriched in the RA synovium. The long range goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy humans but are defective in RA patients. The working hypothesis is that RA B cells suffer from intrinsic BCR signaling defects that impinge on the proper counterselection of developing autoreactive B cells, and result in the abnormal recruitment and activation of peripheral self-reactive B cells into the synovium. The first aim of the project will consist of characterizing the molecular basis for early defects in B cell tolerance checkpoints in RA by comparing microarray gene expression profiles from control and RA B cell subpopulations (whether or not triggered by their BCR) that may reveal specific BCR signaling defects for the different subgroups of RA patients. The second part of the project will identify alternative B cell tolerance mechanisms such as anergy that can substitute for defective receptor editing in humans. The third part of the project will analyze how B cell tolerance is broken in the synovium of RA patients. These studies have significant implications for understanding how people with autoimmune diseases produce antibodies that attack their body and may provide clues for development of new medications.

描述（由申请人提供）：自身抗体是包括类风湿关节炎（RA）在内的大多数自身免疫性疾病的特征，并出现在临床疾病发作之前的血清中，这表明RA的B细胞耐受性早期休息。成功治疗消除B细胞的RA患者的RA患者成功治疗了B细胞在RA中的重要作用。 RA中解释自动反应性B细胞和自身抗体产生的基本机制的定义很差。我们最近通过测试了从单个新移民和成熟的幼稚B细胞克隆的重组抗体的特异性，分析了未经治疗的活性RA患者的B细胞耐受性。 RA患者表现出有缺陷的中心和外周B细胞耐受性检查点，导致农奴反应成熟的幼稚B细胞积累，可能导致RA发病机理。此外，大约一半的RA患者显示出具有缺陷受体编辑的新移民B细胞，这是通常确保B细胞耐受性的三种机制之一。另一半患者表现出新的移民B细胞，具有异常长（11或更多氨基酸）的互补性，确定与自我反应性相关的区域3（CDRSS），发现富集在RA Synovium中。拟议研究的远距离目标是确定调节健康人类B细胞耐受性但在RA患者中有缺陷的机制。工作假设是RA B细胞患有内在的BCR信号传导缺陷，这些缺陷会影响出现自动反应性B细胞的适当反选择，并导致外周自我反应B细胞异常募集和激活进入滑入。该项目的第一个目标将包括表征RA中B细胞耐受性检查点的早期缺陷的分子基础，通过比较来自对照和RA B细胞亚群（是否由其BCR触发）的微阵列基因表达曲线（是否可能揭示了RA患者不同亚基的特定BCR缺陷）。该项目的第二部分将确定替代人类中有缺陷的受体编辑的替代B细胞耐受性机制。该项目的第三部分将分析RA患者滑膜的B细胞耐受性如何破坏。这些研究对了解自身免疫性疾病的人如何产生攻击其身体的抗体具有重要意义，并可能为开发新药物提供线索。