ANTIGEN DRIVEN SELECTION/TOLERANCE: AUTOIMMUNITY TO DNA

描述：(改编自调查人员摘要)：系统性红斑狼疮 红斑狼疮是一种全身性自身免疫性疾病，在人类和遗传上 易患此病的老鼠。针对多种细胞抗原的抗体，主要是核抗原 在小鼠和人类的狼疮血清中检测到了起源；然而， 自身抗体，有最令人信服的病理证据 相关性是针对DNA的抗体。抗DNA抗体在肾脏中沉积为 免疫复合物或通过直接与肾小球结构结合而启动 肾小球肾炎。抗DNA抗体产生的免疫学基础 小鼠和人类的自身抗体一直很难阐明。的目标是 申请者“抗原驱动的选择与耐受性”的研究 对DNA的自身免疫“继续被指向理解如何 对DNA的自身免疫是在个体水平上启动和维持的 自身免疫(NZB×NZW)F1小鼠DNA特异性B细胞申请人的 自上次对该项目进行竞争性审查以来，研究工作已经完成 继续支持对DNA的自身免疫既启动了 并作为克隆选择性、抗原特异性的免疫反应持续存在 DNA很可能以DNA-蛋白质复合体的形式存在。这项研究已经 继续专注于实验，以了解特异度和 体内自身免疫性抗DNA抗体反应的特异性成熟 (NZB×NZW)F1小鼠个体及其DNA多肽诱导的免疫抗DNA 正常小鼠的抗体反应仍在继续。研究结果提供了新的 DNA和V病毒自身免疫应答中B细胞选择的信息 该选择发生所需的区域结构。在申请人的 继续研究以了解对DNA的自身免疫是如何启动的， 他们将检验一种假设，即对DNA的自身免疫是由 外周B细胞缺失时的抗原特异性B细胞刺激 由胞外DNA或核小体诱导的耐受性。具体的 在拟议的研究中要追求的实验目标将是确定 如果有的话，生发中心在特异性成熟中扮演什么角色？ 产生针对天然DNA的高亲和力自身抗体。拟议的实验将 也要确定可溶DNA或核小体在维持 对DNA的免疫耐受。本实验系统设计完成 拟议的研究将包括使用(NZB X NZW)F1转基因小鼠 用于表达抗DNA抗体。这些老鼠有一种有趣的 自身免疫表型，使它们非常适合用来测试 (NZB X NZW)F1小鼠对DNA的自身免疫起源于 缺乏有效外周条件下的抗原选择性B细胞刺激 宽容。

DESCRIPTION: (Adapted from the Investigator's abstract): Systemic lupus erythematosus is a systemic autoimmune disease in humans and genetically predisposed mice. Antibodies to a variety of cellular antigens, mostly nuclear in origin, have been detected in lupus sera from mice and humans; however, the autoantibody for which there is the most compelling evidence for pathological relevance is antibody to DNA. Anti-DNA antibodies deposit in kidneys either as immune complexes or by binding directly to glomerular structures and initiate glomerulonephritis. The immunological basis for the generation of anti-DNA autoantibody in mice and humans has been difficult to elucidate. The goal of the applicant's research on "Antigen Driven Selection and Tolerance in Autoimmunity to DNA" continues to be directed toward understanding how autoimmunity to DNA is initiated and sustained at the level of individual DNA-specific B cells in autoimmune (NZB x NZW) F1 mice. The applicant's research efforts since the last competitive review of this project have continued to support the hypothesis that autoimmunity to DNA is both initiated and sustained as a clonally selective, antigenic-specific immune response to DNA most likely in the form of DNA-protein complexes. The research has continued to focus on experiments to understand how the specificity and specificity maturation of the autoimmune anti-DNA antibody response within individual (NZB x NZW) F1 mice and the DNA-peptide induced immune anti-DNA antibody response in normal mice proceed. The results have provided new information about B cell selection in the autoimmune response to DNA and the V region structures necessary for that selection to occur. In the applicant's continuing research efforts to understand how autoimmunity to DNA is initiated, they will test the hypothesis that autoimmunity to DNA is initiated by antigen-specific B cell stimulation in the absence of peripheral B cell tolerance induced by extracellular DNA or nucleosomes. The specific experimental aims to be pursued in the research proposed will be to determine what role, if any, germinal centers play in the specificity maturation that generates high avidity autoantibodies to native DNA. Proposed experiments will also determine the role of soluble DNA or nucleosomes in maintaining immunological tolerance to DNA. The experimental systems designed to complete the proposed research will include the use of (NZB x NZW) F1 mice transgenic for expression of anti-DNA antibodies. These mice have an interesting autoimmune phenotype that make them highly suited for experiments to test the hypothesis that autoimmunity to DNA in (NZB x NZW) F1 mice derives from antigen-selective B cell stimulation in the absence of effective peripheral tolerance.