B CELL HYPERACTIVITY IN AUTOIMMUNITY

自身免疫中的 B 细胞过度活跃

• 批准号: 3157123
• 负责人: Ann Marshak-Rothstein
• 金额: $ 21.94万
• 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 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3157123
• 关键词: B lymphocyte; alleles; antibody; antibody formation; antigens; autoantibody; autoimmune disorder; cell fusion; disease /disorder model; enzyme linked immunosorbent assay; gene expression; gene mutation; genetic manipulation; genetic strain; graft versus host disease; heterozygote; histocompatibility gene; immunogenetics; immunoglobulin G; immunoglobulin idiotypes; interleukin 2; interleukin 3; laboratory mouse; leukocyte activation /transformation; lymphokines; monoclonal antibody; nephritis; radioimmunoassay; rheumatoid factor; systemic lupus erythematosus; tissue mosaicism

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.

拟议研究的目的是描述基本的 导致 B 细胞过度活跃的免疫机制 自身免疫 MRL/1pr 小鼠模型。 本次活动的主要目标 提议将检查 1pr 突变的直接影响 特定 B 细胞谱系，以评估 驾驶中的多克隆激活和抗原特异性激活 自身抗体的产生，并确定致病性和 类风湿因子对1pr病的免疫调节作用 过程。 将用于解决的具体方法 这些问题将包括： 嵌合小鼠的生产 表达 1pr 突变，其中发育和功能 来自正常和自身免疫混合物的 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性独特型 在自身免疫的情况下使用特定半抗原进行免疫 1pr环境；体内和体外的表征 与单克隆相关的 B 细胞克隆的增殖能力 1pr 小鼠的伽马射线病；能力评估 被动转移单克隆类风湿因子导致 正常小鼠和小鼠中存在 IgG2a 抗体的肾炎 自身免疫小鼠在年轻时注射。 总的来说这些研究 应该有助于我们对机制的基本理解 调节 B 细胞活化和抗体产生。 结果 该建议最终应具有临床应用 关于基本免疫调节缺陷的控制 参与自身免疫性疾病，例如系统性狼疮 红斑狼疮和类风湿性关节炎。