APOPTOSIS-MODIFIED SELF ANTIGEN IN RHEUMATIC DISEASE

产品说明： （改编） 从 申请人的 摘要）： 的 U1 - 70kDa 核糖核蛋白是风湿病患者中的一种普遍的自身抗原， 在凋亡中经历蛋白水解裂解。 自身免疫性疾病模型 提出，修饰形式的自身抗原可以导致识别 先前隐藏的表位，允许自身反应性免疫应答， 进化 因此，免疫修饰的U1 - 70kDa是可以 参与自身免疫性风湿病的演变。 长期 本申请的目的是开发一个独立的研究项目 从而改善风湿性关节炎的诊断、治疗和预防。 疾病，基于 更好地理解 贡献 反相改性 自身抗原 自身免疫的产生 应答 以下具体目的将检查凋亡Ul-70kDa在细胞凋亡中的作用。 自身免疫性疾病。首先，将确定凋亡的Ul-70kDa是否被诱导。 抗原性不同于完整的U1 - 70kDa。 来自完整的 将测试Ul-70kDa抗体的细胞凋亡特异性抗体。 通过ELISA和免疫印迹法检测U 170kDa的形式。从Fab产生的免疫球蛋白 针对凋亡U1 - 70kDa选择的噬菌体表达文库也将被 筛选了结肠癌特异性U1 - 70kDa反应性。表位作图将是 用所有凋亡U1 - 70kDa特异性抗血清和Fab进行鉴定， 抗原的凋亡形式上的免疫学上不同的区域。 其次，在一个大型风湿性疾病患者队列中， 串行 血液样本已被抽取，将确定是否 抗凋亡U170kDa 响应 先于抗完整 Ul-70kDa 免疫 应答 作为这项研究的结果，凋亡U1的贡献 -70kDa表位对风湿性疾病的免疫发病机制的作用将是 阐明。 针对具有抗肿瘤修饰的Ul-70kDa的抗体的测定 与风湿性关节炎诊断和治疗的潜在临床相关性 疾病，将会发展。 在未来，这项工作可能会导致 特异性免疫治疗的发展 的治疗策略 Ul-70kDa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.