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: 8968799
• 负责人: Eric Meffre
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968799
• 关键词: Accounting; Acetylesterase; Affect; Antibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocytes; Blood; Cell physiology; Characteristics; Complement 3d Receptors; Data; Defect; Development; Disease; Evolution; Excision; Flow Cytometry; Frequencies; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Human; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin-6; Investigation; Lasers; Lead; Monoclonal Antibody CD20; PTPN22 gene; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Play; Production; Receptor Signaling; Receptors, Antigen, B-Cell; Recruitment Activity; Refractory; Regulation; Research; Rheumatoid Arthritis; Role; Shapes; Sialic Acids; Structure of germinal center of lymph node; Subgroup; Synovial Membrane; Systemic Lupus Erythematosus; T-Lymphocyte; TNF gene; TNFRSF5 gene; Testing; Work; anergy; ataxia telangiectasia mutated protein; autoreactive B cell; cytokine; design; disorder control; mouse model; novel strategies; prevent; receptor; research study; risk variant

DESCRIPTION (provided by applicant): A role for B cells in autoimmune diseases is now clearly established both with mouse models as well as in humans by successful treatment of rheumatoid arthritis (RA) and other autoimmune diseases with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells may promote the development of autoimmune diseases remain poorly understood. We previously demonstrated that untreated active RA patients, patients with systemic lupus erythematosus, and patients with type 1 diabetes display abnormal early B cell tolerance checkpoints resulting in the accumulation of large numbers of autoreactive naove B cells in their blood. We recently established that these early B cell tolerance defects were primary to these autoimmune diseases and can be induced in asymptomatic donors by risk alleles such as PTPN22, which interfere with B cell receptor (BCR) signaling and the establishment of central B cell tolerance. In addition, anergy, one of the central B cell tolerance mechanisms, seems to be favored in some RA patients as illustrated by the increased frequency of peripheral unresponsive autoreactive B cells, which do not express the complement receptor 2/CD21 and are refractory to BCR and CD40 triggering. Hence, increased numbers of naove autoreactive B cells in patients with RA may favor disease development but it remains to be determined what pathways and mechanisms break B cell tolerance. The long range goal of the proposed research is to continue to characterize 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 defects caused by associated risk alleles, which impinge on sensing self-antigens and result in an altered induction/regulation of central B cell tolerance mechanisms. Hence, receptor editing and deletion fail to be properly regulated in RA patients whereas anergy also contributes to the increased numbers of autoreactive B cells reaching the periphery where inflammatory conditions such as in the synovium may lead the activation of these autoreactive B cells and promote disease development. In addition, understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease and design more specific and sustained therapies.

描述（由申请人提供）：通过使用消除B细胞的抗-CD 20单克隆抗体成功治疗类风湿性关节炎（RA）和其他自身免疫性疾病，现已明确确立了B细胞在自身免疫性疾病中的作用。然而，B细胞可能促进自身免疫性疾病发展的潜在机制仍然知之甚少。我们先前证实，未经治疗的活动性RA患者、系统性红斑狼疮患者和1型糖尿病患者显示异常的早期B细胞耐受检查点，导致大量自身反应性nove B细胞在血液中积聚。我们最近确定这些早期B细胞耐受性缺陷是这些自身免疫性疾病的原发性，并且可以在无症状供体中由风险等位基因如PTPN 22诱导，其干扰B细胞受体（BCR）信号传导和中心B细胞耐受性的建立。此外，无反应性（中枢B细胞耐受机制之一）似乎在某些RA患者中有利，如外周无反应性自身反应性B细胞频率增加所示，其不表达补体受体2/CD 21并且对BCR和CD 40触发不敏感。因此，类风湿关节炎患者中nove自身反应性B细胞数量的增加可能有利于疾病的发展，但仍有待确定是什么途径和机制打破了B细胞耐受性。该研究的长期目标是继续描述在健康人中调节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细胞患有由相关风险等位基因引起的内在缺陷，其冲击感知自身抗原并导致改变的中枢B细胞耐受机制的诱导/调节。因此，受体编辑和缺失在RA患者中未能得到适当调节，而无反应性也有助于增加到达外周的自身反应性B细胞的数量，其中炎性病症（例如滑膜中的炎性病症）可能导致这些自身反应性B细胞的活化并促进疾病发展。此外，了解预防或解释自身反应性B细胞产生的机制可能会提出控制疾病和设计更特异和持续治疗的新方法。

项目成果

Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition.

• DOI: 10.1084/jem.20121486
• 发表时间: 2013-03-11
• 期刊: The Journal of experimental medicine
• 作者: Amara K;Steen J;Murray F;Morbach H;Fernandez-Rodriguez BM;Joshua V;Engström M;Snir O;Israelsson L;Catrina AI;Wardemann H;Corti D;Meffre E;Klareskog L;Malmström V
• 通讯作者: Malmström V