Evolving Adaptive and Effector Mechanisms from Pre-RA Through Established Disease

 描述(申请人提供)：类风湿性关节炎(RA)是一种疾病，从其最早的无症状起源，仅以自身抗体为特征，经过几个阶段的顺序发展，直到完全确定的慢性破坏性关节炎。已建立的类风湿性关节炎还具有几个表型亚群的特征，这些亚群因基因、自身抗体和环境暴露而异。这项临床和技术研究站点(CTRS)建议的中心假设是，RA可以被解构，从而可以通过对免疫系统关联的适应性和效应器臂的综合评估来识别新的疾病阶段和细胞谱系特异性治疗靶点。这项研究反映了对疾病全范围的关注，被命名为EMORA(类风湿性关节炎的演变机制)。总体而言，EMORA临床和技术现场调查人员拥有几个现有的队列和数十年的成功合作，共同构成了一个综合的现场网络，拥有临床研究专业知识、识别和表征抗原特异性淋巴细胞的先进技术，以及使用许多创新技术处理和研究滑膜的能力。EMORA将利用一种核心策略，即以高度协调的方式获取配对的外周血液和滑膜样本并进行研究，T和B淋巴细胞、成纤维细胞样滑膜细胞和单核细胞破骨细胞前体的群体将被评估为单细胞和小的同质群体。使用这些方法，EMORA研究人员将检验三个主要假设：1)可以发现RA的新的发病机制和不同的治疗靶点，这些机制和治疗靶点将随着疾病的发展阶段而变化，范围从早期临床疾病发病的极高风险到已确诊的RA患者 在治疗中，2)将在与RA相关自身抗原反应的抗原特异性循环和组织渗透的B和T细胞中识别治疗靶点，这就需要对外周血液和滑膜进行配对研究，以及3)探索在外周血液和滑膜中发现的滑膜“效应”细胞网络，包括成纤维细胞样滑膜细胞和单核细胞破骨细胞前体，将确定导致炎症、软骨破坏和骨丢失的新途径和相关疾病靶点。最后，为了发展超声引导的滑膜活检技术方面的专业知识，与利兹大学的保罗·埃默里教授共同开发了一个针对美国调查人员的“动手”程序教育和评估计划。

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a disease that sequentially progresses through several stages from its earliest asymptomatic origins characterized by autoantibodies alone through to a fully established and chronic destructive arthritis. Established RA is also characterized by several phenotypic subgroups that vary by genotype, autoantibodies, and environmental exposures. The central hypothesis of this Clinical and Technology Research Site (CTRS) proposal is that RA can be deconstructed such that novel disease stage- and cell lineage-specific therapeutic targets can be identified through the comprehensive evaluation of the linked adaptive and effector arms of the immune system. Reflecting this focus over the full spectrum of disease, the study is designated EMORA (Evolving Mechanisms of Rheumatoid Arthritis). In aggregate, the EMORA clinical and technology site investigators have several existing cohorts and decades of successful collaborations, and together constitute an integrated network of sites with clinical studies expertise, advanced technologies to identify and characterize antigen-specific lymphocytes, and capabilities to process and study synovium using many innovative technologies. EMORA will utilize a core strategy wherein paired peripheral blood and synovial samples are obtained and studied in a highly coordinated manner, and populations of T and B lymphocytes, fibroblast like synoviocytes and monocytic osteoclast precursors will be evaluated as single cells and small homogeneous populations. Using these approaches, EMORA investigators will test three primary hypotheses: 1) Novel mechanisms of disease and distinct therapeutic targets in RA can be discovered that will vary by the stage of development of disease, ranging from subjects at extraordinarily high risk for incipient clinical disease onset through to those with established RA under treatment, 2) Therapeutic targets will be identifiable in both antigen-specific circulating and tissue infiltrating B and T cells that react with RA- related autoantigens, necessitating paire studies of both peripheral blood and synovium, and 3) Exploration of networks of synovial "effector" cells including fibroblast-like synoviocytes and monocytic osteoclast precursors, identified in both peripheral blood and synovium, will identify novel pathways and related disease targets that drive inflammation, cartilage destruction and bone loss. Finally, to develop expertise going forward in ultrasound-guided synovial biopsy techniques, a `hands-on" procedural education and evaluation program for USA investigators has been developed with Professor Paul Emery at the University of Leeds.