B CELL HYPERACTIVITY IN AUTOIMMUNITY

自身免疫中的 B 细胞过度活跃

• 批准号: 6285791
• 负责人: Ann Marshak-Rothstein
• 金额: $ 30.97万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-22 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6285791
• 关键词: B lymphocyte; T lymphocyte; autoantibody; autoantigens; autoimmune disorder; cell cell interaction; genetically modified animals; immunogenetics; immunoglobulin G; immunoregulation; laboratory mouse; leukocyte activation /transformation; rheumatoid factor

DESCRIPTION: (Adapted from the Investigator's abstract): Rheumatoid factors autologous IgG present in the synovial fluid of patients with rheumatoid arthritis. High levels of RF-containing immune complexes and/or cryoglobulins have also been found in patients with microbial infections such as infectious endocarditis, in individuals presenting with hepatitis C-related essential mixed cryogloblulinemia, and in Fas/FasL-deficient (lpr/gld) mice. These immune complexes can deposit in blood vessel walls, fix complement, and thereby promote the vasculitis and glomerulonephritis associated with these diseases. Thus the contribution of RF to the effector arm of systemic autoimmune disease is well documented. Nevertheless, exactly how RF+ B cells become activated, why RF so frequently present as monoclonal gammopathies, and what role RF+ B cells might play in the initiation and propagation of the autoimmune cascade are questions that remain unresolved. The intent of the current application is to address these questions by using an RF+ B cell receptor transgenic mouse line, developed from a prototypic MRL/lpr-derived autoantibody, to evaluate the role RF+ B cells might play in the presentation of autoantigens. Specifically, the project will be organized to: (1) determine the ability of monomeric IgG2a and different types of IgG2a-containing immune complexes to activate RF+ B cells and evaluate the ability of activated and non-activated RF+ B cells to process and present autoantigenic epitopes; (2) evaluate the ability of RF+ B cells to stimulate autoreactive T cells in vitro and determine the specificity of the RF-activated ART; and (3) assess the ability of RF+ B cells and/or RF -activated ART to trigger and propagate systemic autoimmune disease. While dealing with RF in particular, the results of these experiments should be applicable to a more general understanding of the principles governing self/nonself recognition and tolerance induction. Moreover, this experimental strategy should also have direct relevance to human clinical syndromes associated with excessive RF production.

描述：（改编自研究者摘要）：风湿因子 类风湿关节炎患者滑液中存在的自体IgG 关节炎高水平的含RF的免疫复合物和/或cryobacterulins 在微生物感染的患者中也发现， 心内膜炎，在患有丙型肝炎相关基本 混合性冷球蛋白血症和Fas/FasL缺陷（lpr/gld）小鼠。这些免疫 复合物可以存款在血管壁，固定补体，从而 促进与这些疾病相关的血管炎和肾小球肾炎。 因此，RF对系统性自身免疫性疾病的效应臂的贡献 都是有据可查的。然而，RF+ B细胞究竟是如何被激活的，为什么？ RF如此频繁地表现为单克隆丙种球蛋白病，RF+ B细胞的作用是什么 可能在自身免疫级联反应的启动和传播中起作用的是 尚未解决的问题。本申请的目的是 通过使用RF+ B细胞受体转基因小鼠系来解决这些问题， 从原型MRL/lpr衍生的自身抗体开发，以评估 RF+ B细胞可能参与自身抗原的提呈。具体而言是 项目的组织将： (1)确定单体IgG 2a和不同类型的 含IgG 2a的免疫复合物激活RF+ B细胞并评估RF + B细胞的免疫应答。 活化和非活化RF+ B细胞的加工和呈递能力 自身抗原表位;（2）评估RF+ B细胞刺激 自身反应性T细胞在体外，并确定RF激活的特异性 ART;和（3）评估RF+ B细胞和/或RF活化的ART的能力， 引发和传播系统性自身免疫性疾病。在处理RF时， 特别是，这些实验的结果应该适用于更多的 对自我/非自我识别原则的一般理解， 耐受诱导此外，这一实验策略还应具有 与过量RF相关的人类临床综合征直接相关 生产