B CELL HYPERACTIVITY IN AUTOIMMUNITY

拟议研究的目的是勾勒出基本的 B细胞过度活跃的免疫学机制 自身免疫性MRL/1PR小鼠模型。这次会议的主要目标是 建议将检查1PR突变的直接影响 在特定的B细胞谱系上，以评估 驾驶过程中的多克隆激活和抗原特异性激活 自身抗体的产生，并确定致病和 类风湿因子对1PR病的免疫调节作用 进程。将用于解决以下问题的具体方法 这些问题将包括：嵌合小鼠的生产 表达的1PR突变在其中的发育和功能 正常和自身免疫混合来源的B细胞的活性 干细胞将受到监测；B细胞的分子分析 致力于生产以下交叉反应独特型 自身免疫中的特定半抗原免疫 1PR环境；体内和体外的表征 与单抗相关的B细胞克隆的增殖能力 1PR小鼠的GAMMAP病态反应； 被动转移单抗类风湿因子引起 正常及预制IgG2a抗体小鼠肾炎 自体免疫的小鼠在很小的时候注射。总体而言，这些研究 应该有助于我们对这些机制的基本理解 调节B细胞活化和抗体产生。结果是 最终应该会在临床上得到应用 关于基本免疫调节缺陷的控制 与自身免疫性疾病有关，如系统性红斑狼疮 红斑性关节炎和类风湿性关节炎。

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.