AUTOANTIBODIES TO ACTIVATED LYMPHOCYTES IN SLE

SLE 中活化淋巴细胞的自身抗体

• 批准号: 3155911
• 负责人: JOHN B WINFIELD
• 金额: $ 23.53万
• 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 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3155911
• 关键词: B lymphocyte; T lymphocyte; antibody specificity; autoantibody; cell population study; human subject; immune complex; immunoregulation; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; monoclonal antibody; orphan disease /drug; surface antigens; systemic lupus erythematosus; tissue /cell culture

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.

系统性红斑狼疮(SLE)是一种慢性多系统疾病 一种以多种免疫性疾病为特征的疾病 异常，并已成为研究的原型 自身免疫和免疫复合体介导的组织损伤。 大量证据表明，不同类型的 针对淋巴细胞的自身抗体可能是最重要的 关于免疫系统功能障碍在这种疾病中。 过去四年的调查增加了我们的 对静息和活化T细胞靶抗原的认识 这一系统的特殊性，并描绘了几个有趣的 抗淋巴细胞自身抗体影响机制的研究进展 细胞表面抗原表达、T细胞亚群 循环和T细胞激活。虽然在范围上比 最初的申请，本提案的总体目标 继续是对本质和意义的定义 系统性红斑狼疮中的抗淋巴细胞自身抗体。AIM I中的重点是 放在鉴定和生化特性上 自身抗体针对不同细胞类型上的分子。特价 将努力确定抗淋巴细胞是否 抗体反应抗原是碳水化合物，本质上是 在T细胞激活过程中被磷酸化，并附着在 细胞骨架。AIM II的实验将研究抗淋巴细胞 抗体作为激活配体，并将阐明其作用机制(S) 从而抑制T细胞的激活。AIM III涉及 抗淋巴细胞自身抗体与临床的关系 疾病表现和SLE的自然病史。淋巴细胞 以及从患者体内不同时间点获得的血清 疾病，或具有不同临床表现的，将被分析 比较免疫荧光/细胞毒性和Western 吸墨法实验。对这一目标感兴趣的还有实验。 为了确定体内T细胞亚群的耗竭和 内源性T细胞活化在慢性粒细胞增生性疾病中的作用 体外培养。交叉的自身抗体和单抗- 与来自细胞核、细胞质和 AIM IV将使用质膜隔室进行搜索 对于由膜表面靶标共享的同源表位 抗淋巴细胞自身抗体。交叉反应独特型和 抗淋巴细胞抗体Ig的轻链限制将是 也在寻找。病毒感染者体内抗淋巴细胞抗体的检测 感染和非SLE自身免疫性疾病将在#年进行研究 目的为分子模拟(表位)研究提供线索 同源性)，关于SLE的假定微生物触发因素和 相关的障碍。