ANTIGEN DRIVEN SELECTION/TOLERANCE: AUTOIMMUNITY TO DNA

描述：（改编自研究者摘要）：系统性狼疮 红斑狼疮是人类的系统性自身免疫性疾病， 易感小鼠多种细胞抗原的抗体，主要是细胞核抗原 在小鼠和人的狼疮血清中检测到;然而， 自身抗体，其中有最令人信服的证据，病理 相关性是DNA抗体。抗DNA抗体存款在肾脏中， 免疫复合物或通过直接结合到肾小球结构并启动 肾小球肾炎抗DNA抗体产生的免疫学基础 在小鼠和人类中的自身抗体一直难以阐明。的目标 申请人关于“抗原驱动的选择和耐受性， 对DNA的自身免疫”继续致力于了解 对DNA的自身免疫是在个体水平上启动和维持的， 自身免疫（NZ B x NZW）F1小鼠中的DNA特异性B细胞。申请人的 自该项目上次竞争性审查以来， 继续支持这样的假设，即对DNA的自身免疫 并持续作为克隆选择性抗原特异性免疫应答， DNA很可能是以DNA-蛋白质复合物的形式存在。这项研究 继续专注于实验，以了解特异性和 体内自身免疫性抗DNA抗体应答的特异性成熟 单个（NZB x NZW）F1小鼠和DNA-肽诱导的免疫抗-DNA 正常小鼠的抗体应答进行。结果提供了新的 关于B细胞在自身免疫应答中对DNA和V 选择所需的区域结构。在申请人的 继续研究努力，以了解如何启动对DNA的自身免疫， 他们将检验对DNA的自身免疫是由 在缺乏外周B细胞的情况下的抗原特异性B细胞刺激 细胞外DNA或核小体诱导的耐受性。具体 在拟议的研究中，将追求的实验目标是确定 如果有的话，生发中心在特异性成熟中起什么作用， 产生对天然DNA的高亲合力自身抗体。拟议的实验将 还确定了可溶性DNA或核小体在维持 对DNA免疫耐受。设计的实验系统 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。这些老鼠有一个有趣的 自身免疫表型，使他们非常适合实验，以测试 假设（NZB x NZW）F1小鼠中对DNA的自身免疫来自于 抗原选择性B细胞刺激，在缺乏有效的外周 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.