Activation and Regulation of Rheumatoid Factor B cells

类风湿因子 B 细胞的激活和调节

• 批准号: 6535334
• 负责人: MARK J SHLOMCHIK
• 金额: $ 16.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2002-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6535334
• 关键词: B lymphocyte; antibody formation; autoantibody; autoimmune disorder; autoimmunity; genetically modified animals; immunoregulation; laboratory mouse; leukocyte activation /transformation; rheumatoid factor

DESCRIPTION (provided by investigator): Autoreactive B cells are the source of pathogenic autoantibodies and are critical APCs for the stimulation of autoreactive T cells. Hence, it is fundamentally important to understand how these B cells develop, are regulated in normal animals, and escape self-tolerance during autoimmunity. This has been the major long-term focus of our lab. Immunoglobulin transgenic (Ig-Tg) mouse systems have been invaluable in efforts to address these questions. To understand the regulation of anti-IgG autoantibodies (Rheumatoid Factors, RF), we have created an Ig-Tg model called AM14. AM14 recognizes only IgG2a of the a allotype (IgG2a"a") and not of IgG2a"b". Thus we have used allotype congenic mice to control the presence or absence of the autoAg. B cells appear clonally ignorant in normal AM14 Tg mice. However, AM14 RF B cells are induced over time to become AFC's only when the Tgs are crossed onto autoimmune-prone backgrounds that have the autoAg. Thus, AM14 is a model system in which the loss of tolerance to a relevant autoAg can be readily observed and studied. In addition we have found unexpectedly that somatic hypermutation and selection are occurring in unusual populations of B cells proliferating and differentiating outside of germinal centers, at the outer PALS area. A major limitation in the study of spontaneous autoimmunity is the stochastic onset of autoimmunity; the timing and nature of autoantibodies can vary widely even among littermates of the same inbred strain. Recently we have discovered a method to circumvent these problems in the AM14 system: we found that the appearance of AM14 Id+ B cells in the peripheral blood of autoimmune-prone H-only Tg mice indicates the recent onset of proliferation and differentiation-i.e. autoimmunity-in the spleens of these mice. Serially tracking cohorts of H Tg mice reveals when these cells appear in the PBL for the first time and thus, the onset of autoimmunity. From this point, the mice can be analyzed, treated, or followed to study the further evolution of disease. Here we propose to use this system to: 1) Determine the factors-environmental and genetic-that are required for the onset and early propagation of disease (expansion of autoreactive RF B cells); 2) Define the cascade of events that leads from an initial nidus proliferating autoreactive B cells to chronic, ongoing disease; 3) Determine the identities, at the phenotypic and molecular level, of the unique B lineage cells that that have escaped peripheral tolerance.

描述（由研究者提供）：自身反应性B细胞是致病性自身抗体的来源，是刺激自身反应性T细胞的关键apc。因此，了解这些B细胞如何发育、在正常动物中如何被调节以及在自身免疫过程中如何逃避自身耐受性是至关重要的。这一直是我们实验室长期关注的重点。免疫球蛋白转基因（Ig-Tg）小鼠系统在解决这些问题的努力中是无价的。为了了解抗igg自身抗体（类风湿因子，RF）的调节，我们创建了一个名为AM14的igg - tg模型。AM14只识别a等位型的IgG2a （IgG2a“a”），而不识别IgG2a“b”。因此，我们使用同种异型基因小鼠来控制自体抗原的存在或缺失。正常AM14 Tg小鼠的B细胞表现为无性克隆。然而，随着时间的推移，AM14 RF B细胞只有当Tgs交叉到具有自身ag的自身免疫易感性背景中时才会被诱导成为AFC细胞。因此，AM14是一个模型系统，可以很容易地观察和研究对相关自ag的容差损失。此外，我们还意外地发现，在生发中心外的外PALS区域增殖和分化的不寻常的B细胞群体中发生了体细胞超突变和选择。