APOPTOSIS-MODIFIED SELF ANTIGEN IN RHEUMATIC DISEASE

描述：(改编自申请者S摘要)：U1-70 kDa 核糖核蛋白，风湿病患者中普遍存在的自身抗原， 在细胞凋亡中经历蛋白水解性切割。一种自身免疫性疾病的模型 提出修饰形式的自身抗原可以导致识别 以前神秘的表位，允许自动反应免疫反应 进化。因此，经凋亡修饰的Ul-70 kDa是一种候选抗原，可能 参与自身免疫性风湿病的演变。长期的 此应用程序的目标是开发一个独立的研究计划 这将改善风湿病的诊断、治疗和预防 基于对疾病的贡献的更好的理解 细胞凋亡修饰的自身抗原与自身免疫的产生 回应。 以下具体目标将研究凋亡的Ul-70 kDa在 自身免疫性疾病。首先，将确定凋亡的Ul-70 kDa是否 在抗原性上不同于完整的Ul-70 kDa。完好无损患者的血清 将检测UL-70 kDa抗体以检测针对细胞凋亡的特异性抗体 经酶联免疫吸附试验和免疫印迹法鉴定为U170 kDa。Fab产生的免疫球蛋白 针对凋亡Ul-70 kDa筛选的噬菌体表达文库也将 筛选细胞凋亡特异的Ul-70 kDa反应性。表位映射将是 用所有凋亡的Ul-70 kDa特异性抗血清和Fab进行鉴定 抗原的凋亡型上免疫上不同的区域。 第二，在一大群风湿病患者中， 已经抽取了连续的血样，将确定是否 抗凋亡U170 kDa应答先于抗完整Ul-70 kDa免疫 回应。作为这项研究的结果，凋亡的U1的贡献 -风湿性疾病免疫发病机制的70 kDa表位 已澄清。细胞凋亡性修饰Ul-70 kDa抗体的检测 风湿性疾病的诊断和治疗的潜在临床意义 疾病，将被开发出来。在未来，这项工作可能会导致 特异免疫治疗策略的研究进展 UL-70 kDa相关的风湿性疾病。

DESCRIPTION: (adapted from applicant s abstract): The U1-70kDa ribonucleoprotein, a prevalent autoantigen in rheumatic disease patients, undergoes proteolytic cleavage in apoptosis. A model of autoimmune diseases proposes that modified forms of self antigens can lead to recognition of previously cryptic epitopes, allowing an auto-reactive immune response to evolve. Thus, apoptotically modified Ul-70kDa is a candidate antigen that may be involved in the evolution of autoimmune rheumatic diseases. The long-term objective of this application is to develop an independent program of research that leads to improved diagnosis, treatment, and prevention of rheumatic diseases, based on an improved understanding of the contribution of apoptotically modified self antigens to the generation of autoimmune responses. The following specific aims will examine the role of apoptotic Ul-70kDa in autoimmune disease. First, it will be determined whether apoptotic Ul-70kDa is antigenically distinct from intact Ul-70kDa. Sera from patients with intact Ul-70kDa antibodies will be tested for antibodies specific for the apoptotic form of U170kDa by ELISA and immunoblot. Immunoglobulins generated from Fab phage expression libraries selected against apoptotic Ul-70kDa will also be screened for apoptosis-specific Ul-70kDa reactivity. Epitope mapping will be performed with all apoptotic Ul-70kDa specific antisera and Fab to identify the immunologically distinct areas on the apoptotic form of the antigen. Second, in a large cohort of rheumatic disease patients from whom multiple serial blood samples have been drawn, it will be determined whether anti-apoptotic U170kDa responses precede anti-intact Ul-70kDa immune responses. As a result of this research, the contribution of apoptotic U1 -70kDa epitopes to the immunopathogenesis of rheumatic diseases will be elucidated. Assays for antibodies to apoptotically modified Ul-70kDa with potential clinical relevance to the diagnosis and management of rheumatic diseases, will be developed. In the future, this work may lead to the development of specific immunotherapy strategies for the treatment of Ul-70kDa-associated rheumatic disorders.