AUTOANTIBODIES TO ACTIVATED LYMPHOCYTES IN SLE

系统性红斑狼疮（SLE）是一种慢性多系统性红斑狼疮， 一种以多种免疫反应为特征的疾病 异常，并已成为研究的原型， 自身免疫和免疫复合物介导的组织损伤。 大量证据表明，不同类型的 淋巴细胞自身抗体可能具有根本的重要性 与免疫系统功能紊乱有关。 过去四年的调查增加了我们的 对静息和活化T细胞靶抗原的理解 在这个系统中的特殊性，并描绘了几个有趣的 抗淋巴细胞自身抗体影响 细胞表面抗原表达，T细胞群在 循环和T细胞活化。 虽然范围比 本提案的总体目标 仍然是定义的性质和意义， SLE患者的抗淋巴细胞自身抗体 目标I的重点是 放置在鉴定和生化表征 自身抗体靶向不同细胞类型的分子。 特别 将努力确定抗淋巴细胞 抗体反应性抗原本质上是碳水化合物， 在T细胞活化过程中磷酸化，并连接到 细胞骨架 目的II实验将研究抗淋巴细胞 抗体作为激活配体，并将阐明机制 从而抑制T细胞活化。 目标三： 抗淋巴细胞自身抗体与临床的关系 疾病表达和SLE的自然史。 淋巴细胞 和血清从患者在不同的时间点， 疾病，或具有临床上不同的表现，将进行分析 在比较免疫荧光/细胞毒性和Western 印迹实验。 在这个目标中， 以确定体内T细胞亚群消耗和 内源性T细胞活化导致低增殖， 体外 自身抗体和单克隆抗体交叉- 与来自细胞核、细胞质和 在Aim IV中，将使用质膜隔室来搜索 对于由膜表面靶共享的同源表位， 抗淋巴细胞自身抗体。 交叉反应性独特型和 抗淋巴细胞抗体IG的轻链限制将被 也在寻找。 病毒感染者的抗淋巴细胞抗体 感染和非SLE自身免疫性疾病将在 目的为分子模拟（表位）提供线索 同源性），关于SLE的假定微生物触发剂， 相关疾病。

Systemic lupus erythematosus (SLE) is a chronic multisystem disease characterized by a variety of immunological abnormalities, and has become a prototype for study of autoimmunity and immune complex-mediated tissue injury. Considerable evidence suggests that different types of autoantibodies to lymphocytes may be of fundamental importance with respect to immune system dysfunction in this disorder. Investigation during the past four years has increased our understanding of resting and activated T cell target antigen specificities in this system, and has delineated several interesting mechanisms by which anti-lymphocyte autoantibodies influence cell surface antigen expression, T cell populations in the circulation, and T cell activation. While broader in scope than the original application, the overall objective of the present proposal continues to be the definition of the nature and significance of anti-lymphocyte autoantibodies in SLE. Emphasis in Aim I is placed on the identification and biochemical characterization of autoantibody target molecules on different cell types. Special effort will be made to determine whether anti-lymphocyte antibody-reactive antigens are carbohydrate in nature become phosphorylated during T cell activation, and are attached to the cytoskeleton. Experiments in Aim II will study anti-lymphocyte antibodies as activation ligands, and will clarify the mechanism(s) by which they inhibit T cell activation. Aim III concerns the relationship of anti-lymphocyte autoantibodies with clinical disease expression and the natural history of SLE. Lymphocytes and serum obtained from patients at different points in their illness, or with clinically distinct manifestations, will be analyzed in comparative immunofluorescence/cytotoxicity and Western blotting experiments. Also of interest in this aim are experiments to determine whether in vivo T cell subset depletion and endogenous T cell activation contribute to hypoproliferation in vitro. Autoantibodies and monoclonal antibodies which cross- react with cellular constituents from nuclear, cytoplasmic and plasma membrane compartments will be used in Aim IV to search for homologous epitopes shared by membrane surface targets of anti-lymphocyte autoantibodies. Cross-reactive idiotypes and light chain restriction of anti-lymphocyte antibody Ig will be sought as well. Anti-lymphocyte antibodies in patients with virus infections and non-SLE auto-immune diseases will be studied in Aim V to provide clues, vis a vis molecular mimicry (epitope homology), regarding putative microbial triggers of SLE and related disorders.