AUTOANTIBODIES TO ACTIVATED LYMPHOCYTES IN SLE

SLE 中活化淋巴细胞的自身抗体

• 批准号: 2078726
• 负责人: JOHN B WINFIELD
• 金额: $ 26.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2078726
• 关键词: B lymphocyte; CD antigens; T cell receptor; T lymphocyte; affinity chromatography; autoantibody; biological signal transduction; calcium flux; carbohydrate sequence; chimeric proteins; human subject; immunoglobulin M; leukocyte activation /transformation; longitudinal human study; monoclonal antibody; phosphorylation; protein isoforms; protein sequence; rheumatic fever; systemic lupus erythematosus; tissue /cell culture

The long-term objective of the proposed research is to define the mechanisms by which antilymphocyte autoantibodies contribute to the pathogenesis of SLE, a prototype systemic autoimmune disorder. Of special interest in this regard is our recent discovery that IgM autoantibodies in SLE are directed against different isoforms of CD45, the major protein tyrosine phosphatase on the surface of hemopoietic cells. CD45 recently has been implicated in the regulation of lymphocyte functional activity, including cytotoxicity, proliferation, and differentiation via interaction of its variable extracellular domains with as yet undefined ligands and through its phosphatase action on intracellular tyrosine kinases and other substrates. The identification of different isoforms of CD45 as specific antilymphocyte autoantibody targets should permit a more precise understanding of the mechanisms by which such autoantibodies influence lymphocyte behavior. We hypothesize, therefore, that anti-CD45 autoantibodies contribute to abnormal lymphocyte function in SLE and, possibly, other autoimmune disorders. Experiments in aim 1 will focus on characterizing the nature of CD45 autoreactivity in SLE, especially with respect to delineation of carbohydrate versus polypeptide reactivity. With this information, anti-CD45 autoantibodies will be isolated from SLE serum for functional experiments by affinity chromatographic procedures using CD45 fusion proteins or CD45 purified biochemically from bulk cell preparations. Emphasis in aim 2 will be on the capacity of purified anti- CD45 autoantibodies to influence proximal signal transduction and late activation events in T cells and other types of cells following defined stimulations in vitro. Aim 3 will involve longitudinal studies of clinically and immunologically defined patients, with special reference to the relationship of anti-CD45 autoantibodies with disease activity status and immunologic function. A cross-sectional survey of anti-CD45 autoantibodies in other rheumatic and autoimmune disease sera also will be performed to define the specificity of this autoantibody system for SLE and to determine the prevalence of anti-CD45 autoantibodies in other disorders. Because CD45 is not the only antilymphocyte autoantibody specificity in SLE, efforts to identify and to determine the significance of other targets will be pursued in aim 4 as well.

拟议研究的长期目标是确定 抗淋巴细胞自身抗体促进 SLE是一种典型的全身性自身免疫性疾病。 特殊 在这方面感兴趣的是我们最近发现， SLE是针对不同亚型的CD45，主要蛋白质 造血细胞表面的酪氨酸磷酸酶。 CD45最近 与淋巴细胞功能活性的调节有关， 包括细胞毒性、增殖和通过相互作用的分化 其可变的胞外结构域与尚未定义的配体， 通过其对细胞内酪氨酸激酶和其他 印刷受体. 鉴定不同亚型的CD45作为特异性 抗淋巴细胞自身抗体靶点应该允许更精确的 了解这种自身抗体影响的机制 淋巴细胞行为 因此，我们假设抗CD45 自身抗体导致SLE中淋巴细胞功能异常， 可能还有其他自身免疫性疾病 目标1的实验将集中于 表征SLE中CD 45自身反应性的性质，尤其是在 关于描绘碳水化合物对多肽的反应性。 与 根据这些信息，将从SLE血清中分离抗CD45自身抗体 对于通过亲和色谱程序进行的功能实验， CD45融合蛋白或从散装细胞中生物化学纯化的CD45 准备工作。 目标2的重点将是纯化的抗- CD45自身抗体影响近端信号转导和晚期信号转导 T细胞和其他类型细胞中的活化事件， 体外刺激。 目标3将涉及以下纵向研究： 临床和免疫学定义的患者，特别是 抗CD45自身抗体与疾病活动性关系 和免疫功能。 抗CD45抗体的横断面调查 其他风湿性和自身免疫性疾病血清中的自身抗体也将被 进行以确定该自身抗体系统对SLE的特异性， 以确定抗CD45自身抗体在其他疾病中的患病率。 因为CD45不是唯一的抗淋巴细胞自身抗体特异性， SLE，努力识别和确定其他目标的重要性 也将在目标4中加以实现。