Loss of B Cell Tolerance in Primary Immunodeficiencies

原发性免疫缺陷导致 B 细胞耐受性丧失

• 批准号: 6847373
• 负责人: Eric Meffre
• 金额: $ 21.45万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847373
• 关键词: B cell receptor; B lymphocyte; CD40 molecule; antibody; autoimmunity; biological signal transduction; cell differentiation; clinical research; enzyme linked immunosorbent assay; genetic recombination; human subject; immune tolerance /unresponsiveness; immunodeficiency; immunoglobulin M; polymerase chain reaction; recombinase

Antibodies are generated during early B cell development by random joining of immunoglobulin (Ig) gene segments. Ig gene recombination can result in the assembly of self-reactive antibodies or B cell receptors (BCR). B cells that develop self-reactive receptors can be silenced by one of three mechanisms: deletion, anergy; and receptor editing. Whereas deletion and anergy ultimately eliminate self-reactive B cells, receptor editing rescues them by replacing autoreactive antibodies. We analyzed how B cell tolerance was established in humans by following the evolution of autoantibody-producing B cells during B cell development. We found that 55-75% of early B cell precursors expressed self-reactive antibodies and that autoantibodyproducing B cells in healthy donors were removed from the population at two discrete checkpoints. The mechanisms that prevail in silencing these autoreactive B cells remain to be characterized, and little is known about the effect of antibody specificity and BCR signaling in regulating the balance between deletion, anergy, and receptor editing. However, defects in BCR signaling have been reported in B cells from patients with systemic lupus erythematosus and common variable immunodeficiency (CVID) who frequently develop autoimmunity suggesting that BCR signaling may play a role in counterselecting self-reactive B cells. The long range goal of the proposed research is to elucidate the role of BCR in the regulation of B cell tolerance by analyzing primary immunodeficient patient B cells with altered BCR signaling. The working hypothesis is that BCR signaling is essential in establishing B cell tolerance and when it is affected, autoreactive B cells are not silenced and can migrate to the periphery. The first aim of the project will consist of cloning antibodies from single B cells from the blood of X-linked agammaglobulinemia patients and determine whether modified threshold of BCR signaling in btk gene-deficient B cells impacts B cell tolerance mechanisms. The second part of the project will analyze how BCR co-receptors such as CD40 influence the establishment and the maintenance of B cell tolerance in hyper-IgM patients. The third part of the project will study B cell tolerance in CVID patients. These studies have significant implications for understanding how self-reactive B cells may be produced with or without maintaining self-tolerance.

抗体是在早期 B 细胞发育过程中通过随机连接免疫球蛋白 (Ig) 基因片段而产生的。 Ig 基因重组可导致自身反应性抗体或 B 细胞受体 (BCR) 的组装。产生自身反应性受体的 B 细胞可以通过以下三种机制之一来沉默：缺失、无反应；和受体编辑。缺失和无反应最终消除了自身反应性 B 细胞，而受体编辑则通过替换自身反应性抗体来拯救它们。我们通过跟踪 B 细胞发育过程中产生自身抗体的 B 细胞的进化，分析了人类如何建立 B 细胞耐受性。我们发现 55-75% 的早期 B 细胞前体表达自身反应性抗体，并且产生自身抗体 健康捐献者的 B 细胞在两个离散的检查点从群体中去除。这 沉默这些自身反应性 B 细胞的主要机制仍有待表征，而且对于抗体特异性和 BCR 信号传导在调节缺失、无反应性和受体编辑之间的平衡方面的影响知之甚少。然而，据报道，系统性红斑狼疮和常见变异型免疫缺陷 (CVID) 患者的 B 细胞存在 BCR 信号传导缺陷，这些患者经常发生自身免疫，这表明 BCR 信号传导可能在反选择自身反应性 B 细胞中发挥作用。 该研究的长期目标是通过分析具有改变的 BCR 信号传导的原代免疫缺陷患者 B 细胞，阐明 BCR 在 B 细胞耐受调节中的作用。目前的假设是，BCR 信号传导对于建立 B 细胞耐受性至关重要，当它受到影响时，自身反应性 B 细胞不会被沉默，并且可以迁移到外周。该项目的第一个目标将包括从 X 连锁无丙种球蛋白血症患者血液中的单个 B 细胞中克隆抗体，并确定 btk 基因缺陷 B 细胞中 BCR 信号传导阈值的修改是否会影响 B 细胞耐受机制。该项目的第二部分将分析 CD40 等 BCR 辅助受体如何影响高 IgM 患者 B 细胞耐受的建立和维持。该项目的第三部分将 研究 CVID 患者的 B 细胞耐受性。这些研究对于了解在维持或不维持自我耐受的情况下如何产生自我反应性 B 细胞具有重要意义。