B CELL HYPERACTIVITY IN AUTOIMMUNITY

描述：(改编自《调查者摘要》)：类风湿因子 类风湿患者滑液中存在自体免疫球蛋白 关节炎。高水平的含RF免疫复合体和/或冷冻球蛋白 也在患有微生物感染的患者中发现，如传染性 表现为丙型肝炎相关基本症状的个体中的心内膜炎 混合冷球蛋白血症，以及Fas/FasL缺陷(LPR/GLD)小鼠。这些免疫 复合体可以沉积在血管壁中，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在系统性自身免疫性疾病效应臂中的作用 都有很好的记录。然而，RF+B细胞究竟是如何被激活的，为什么 RF如此频繁地以单克隆性伽马病的形式出现，RF+B细胞在其中扮演什么角色 可能在自身免疫级联反应的启动和传播中发挥作用 仍未解决的问题。当前应用程序的目的是 通过使用RF+B细胞受体转基因小鼠系来解决这些问题， 从一种原型MRL/LPR衍生的自身抗体开发，以评估其作用 RF+B细胞可能参与自身抗原的提呈。具体地说， 该项目将被组织为： (1)测定单体IgG2a和不同类型的 含IgG2a免疫复合物激活RF+B细胞的实验研究 激活和非激活的RF+B细胞处理和呈递的能力 自身抗原表位；(2)评价RF+B细胞的刺激能力 自身反应性T细胞的体外培养及RF激活的特异性测定 ART；和(3)评估RF+B细胞和/或RF激活的ART的能力 引发和传播系统性自身免疫性疾病。在处理射频输入时 特别是，这些实验的结果应该更适用于 对自我/非我认识原则的一般理解和 耐受性诱导。此外，这个试验性的策略也应该有 与RF过多相关的人类临床症状的直接相关性 制作。

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.