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; 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.

通过免疫球蛋白（IG）基因段的随机连接在早期B细胞发育过程中产生抗体。 Ig基因重组会导致自反应性抗体或B细胞受体（BCR）组装。产生自我反应受体的B细胞可以通过三种机制之一来保持沉默：缺失，无反应；和受体编辑。而删除和消极最终消除了自反应的B细胞，而受体编辑通过替换自动反应性抗体来挽救它们。我们通过遵循B细胞发育过程中产生自身抗体的B细胞的进化来分析在人类中如何建立B细胞的耐受性。我们发现55-75％的早期B细胞前体表达了自反应性抗体，并且自身抗体生产 在两个离散检查点中，将健康供体中的B细胞从人群中删除。这 沉默这些自动反应性B细胞的机制仍有待表征，并且对抗体特异性和BCR信号传导在调节缺失，不良和受体编辑之间的平衡的影响知之甚少。然而，已经报道了来自全身性红斑狼疮患者的B细胞中BCR信号传导的缺陷和常见的可变免疫缺陷（CVID），这些免疫缺陷（CVID）经常发展自身免疫性，这表明BCR信号可能在反反应性B细胞中发挥作用。 拟议研究的远距离目标是通过分析因BCR信号改变的原发性免疫缺陷患者B细胞来阐明BCR在调节B细胞耐受性中的作用。工作假设是，BCR信号对于建立B细胞的耐受性至关重要，并且在受影响时，自动反应性B细胞不会沉默，并且可以迁移到周围。该项目的第一个目的是由来自X连锁Agammagloblobloblobloblobloinemia患者血液中的单个B细胞的克隆抗体组成，并确定BTK基因缺陷型B细胞中BCR信号传导的修饰阈值是否会影响B细胞耐受机制。该项目的第二部分将分析BCR共受体（例如CD40）如何影响Hyper-IGM患者B细胞耐受性的建立和维持。该项目的第三部分将 研究CVID患者的B细胞耐受性。这些研究对了解如何在不保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。