MECHANISMS OF AUTOREACTIVITY IN SLE

SLE 自身反应性机制

• 批准号: 3155426
• 负责人: ROBERT A. EISENBERG
• 金额: $ 17.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-12-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3155426
• 关键词: B lymphocyte; T lymphocyte; antibody specificity; antinuclear autoantibody; autoantigens; autoimmune disorder; disease /disorder model; genetic strain; glomerulonephritis; human subject; immune complex; immunogenetics; orphan disease /drug; radioimmunoassay; rheumatoid arthritis; systemic lupus erythematosus; tissue /cell culture; B lymphocyte; T lymphocyte; antibody specificity; antinuclear autoantibody; autoantigens; autoimmune disorder; disease /disorder model; genetic strain; glomerulonephritis; human subject; immune complex; immunogenetics; orphan disease /drug; radioimmunoassay; rheumatoid arthritis; systemic lupus erythematosus; tissue /cell culture

Anti-Sm antibodies are a highly specific marker for the diagnosis of SLE in humans and in certain SLE mouse strains. The expression of these autoantibodies is under genetic control in mice, although the nature of this control is not at present understood. In addition, the expression of anti-Sm antibodies in a genetically predisposed mouse depends on stochastic processes. The current studies are organized around the working hypothesis that the initiation of the anti-Sm response in individually genetically predisposed animals results from the rearrangement or somatic mutation of unique variable region genes (either light chain or heavy chain). Once the response is initiated, it is amplified by an (?abnormal) antibody-mediated positive feedback mechanism which results in an enhancement of the response and a diversification, either through somatic mutation or through the recruitment of new clones. The genetic predisposition to the anti-Sm response probably relates to a susceptibility to severe SLE, even through the antibody itself is not directly pathogenic. In the current proposal, we will investigate the genetics of the anti-Sm response by crossing anti-Sm positive and anti-Sm negative SLE mouse strains. We will breed anti-Sm positive and anti-Sm negative congenic mouse strains. We will compare the spontaneous anti-Sm response to the passive antibody-induced anti-Sm response, as well as to anti-Sm response induced by the injection of purified Sm in adjuvant. We will also investigate the control of expression of the anti-Sm trait in genetically predisposed strains by determining the repertoire of immunoglobulin variable region genes utilized in this response, and the role that somatic mutation plays. We will look at the expression of anti-Sm antibodies in allotype heterozygous animals in order to determine clonality of the anti-Sm response and changes in clonality over time. Finally, we will study an unusual system of positive feedback caused by passive administration of anti-Sm antibody, which may be important in the development of the high titer anti-Sm response seen in individual positive animals.

抗SM抗体是用于诊断SLE的高度特异性标记 人类和某些SLE小鼠菌株。 这些的表达 自身抗体在小鼠的遗传控制下，尽管 目前尚未理解这种控制。 另外，表达 遗传易感小鼠中的抗SM抗体取决于随机 过程。 目前的研究是围绕工作假设进行的 在遗传上启动抗SM响应 诱发的动物是由重排或躯体突变引起的 独特的可变区域基因（轻链或重链）。 一旦 响应是启动的，它通过（异常）抗体介导的放大 积极的反馈机制，导致反应增强 以及通过躯体突变或通过 招募新克隆。 抗SM的遗传易感性 响应可能与严重SLE的敏感性有关，即使 抗体本身不是直接的致病性。 在当前的提议中 我们将通过跨越抗SM反应的遗传学 抗SM阳性和抗SM负SLE小鼠菌株。 我们将繁殖 抗SM阳性和抗SM阴性小鼠菌株。 我们将 比较自发性抗SM对被动抗体诱导的反应 抗SM反应以及注射引起的抗SM反应 在佐剂中纯化的SM。 我们还将调查对 抗SM性状在遗传性易感性菌株中的表达 确定利用的免疫球蛋白可变区域基因的曲目 在这种反应以及躯体突变扮演的作用中。 我们会看的 在同型杂合动物中抗SM抗体的表达 为了确定抗SM响应的克隆性和变化 随着时间的流逝。 最后，我们将研究一个不寻常的积极系统 由被动施用抗SM抗体引起的反馈，这可能是 对于在高滴度的抗SM反应的发展中很重要 单个积极动物。