AUTOANTIBODIES TO ACTIVATED LYMPHOCYTES IN SLE

拟议研究的长期目标是界定 抗淋巴细胞自身抗体作用机制的研究进展 系统性自身免疫性疾病的原型--SLE的发病机制。特别之处 在这方面的兴趣是我们最近发现，IgM自身抗体在 系统性红斑狼疮针对主要蛋白质CD45的不同亚型。 造血细胞表面的酪氨酸磷酸酶。CD45最近 与淋巴细胞功能活动的调节有关， 包括细胞毒性、增殖和通过相互作用而分化 它的可变胞外域具有尚未定义的配体和 通过其对细胞内酪氨酸激酶等的磷酸酶作用 底物。CD45不同亚型的特异性鉴定 抗淋巴细胞自身抗体靶标应该允许更精确的 对这种自身抗体影响机制的理解 淋巴细胞行为。因此，我们假设，抗CD45抗体 自身抗体导致SLE患者淋巴细胞功能异常， 可能是其他自身免疫性疾病。目标1中的实验将集中在 系统性红斑狼疮患者CD45自身反应性的特征 关于碳水化合物与多肽反应性之间的关系。使用 根据这一信息，将从SLE血清中分离出抗CD45自身抗体 通过使用亲和层析程序进行功能实验 CD45融合蛋白或从散装细胞中生化纯化的CD45 准备工作。目标2的重点将是纯化的抗-HBs的能力 CD45自身抗体对近端信号转导和晚期的影响 定义的T细胞和其他类型细胞中的激活事件 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状态的关系 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 以确定该自身抗体系统对SLE和 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，努力确定和确定其他目标的重要性 也将在目标4中继续进行。

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.