B CELL HYPERACTIVITY IN AUTOIMMUNITY

拟议研究的目的是描绘基本的 免疫机制负责B细胞过度活跃， 自身免疫性MRL/1 pr小鼠模型。 本项目的主要目标是 我们的建议是研究1 pr突变的直接影响， 对特定B细胞谱系的作用，以评估 多克隆激活和抗原特异性激活 自身抗体的产生，并确定致病性和 类风湿因子对1 pr疾病的免疫调节作用 过程 将用于解决以下问题的具体办法： 这些问题将包括：嵌合小鼠的生产 表达1 pr突变，在该突变中， 来源于正常和自身免疫混合物的B细胞的活性 将监测干细胞; B细胞的分子分析 致力于产生交叉反应的独特型， 在自身免疫性疾病的情况下用特异性半抗原免疫 1 pr环境;体内和体外的表征 与单克隆抗体相关的B细胞克隆的增殖能力 1 pr小鼠中的γ病; 被动转移的单克隆类风湿因子 在正常小鼠中用预先形成的IgG 2a抗体进行肾炎， 在幼年时注射的自身免疫小鼠。 总体而言， 应该有助于我们对 调节B细胞活化和抗体产生。 结果 这一建议最终应具有临床应用， 关于基本免疫调节缺陷的控制 与自身免疫性疾病如系统性狼疮有关 红斑和类风湿性关节炎。

The purpose of the proposed study is to delineate the basic immunological mechanisms responsible for B cell hyperactivity in the autoimmune MRL/1pr mouse model. The major goals of this proposal will be to examine the direct effect of the 1pr mutation on specific B cell lineages, to assess the relative roles of polyclonal activation and antigen specific activation in driving autoantibody production, and to determine the pathogenic and immunoregulatory effects of rheumatoid factors on the 1pr disease process. The specific approaches that will be used to address these issues will include: the production of chimeric mice expressing the 1pr mutation in which the development and functional activity of B cells derived from a mixture of normal and autoimmune stem cells will be monitored; the molecular analysis of B cells committed to the production of a crossreactive idiotype following immunization with specific hapten in the context of an autoimmune 1pr environment; the characterization of the in vivo and in vitro proliferative capacity of B cell clones associated with monoclonal gammapathies in 1pr mice; the assessment of the ability of passively transferred monoclonal rheumatoid factors to cause nephritis in mice with preformed IgG2a antibody in normal and autoimmune mice injected at a young age. Overall these studies should contribute to our basic understanding of the mechanisms regulating B cell activation and antibody production. The results of this proposal should eventually have clinical application with regard to the control of the basic immunoregulatory defects involved in autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis.