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

 描述（由申请人提供）：类风湿性关节炎（RA）是一种疾病，从最早期的无症状起源（特征为单独的自身抗体）到完全确立的慢性破坏性关节炎，依次进展几个阶段。已确诊的RA还具有几个表型亚组的特征，这些亚组因基因型、自身抗体和环境暴露而异。该临床和技术研究中心（CTRS）提案的中心假设是，RA可以被解构，从而可以通过对免疫系统的相关适应性和效应臂的综合评价来识别新的疾病阶段和细胞系特异性治疗靶点。为了反映这种对疾病全谱的关注，这项研究被命名为EMORA（风湿性关节炎的演变机制）。总体而言，EMORA临床和技术研究中心研究者拥有多个现有队列和数十年的成功合作，共同构成了一个综合的研究中心网络，该网络具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将采用核心策略，其中以高度协调的方式获得配对的外周血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作为单细胞和小型同质群体进行评价。使用这些方法，EMORA研究人员将测试三个主要假设：1）可以发现RA的新疾病机制和不同的治疗靶点，这些机制和靶点随疾病发展阶段而变化，从早期临床疾病发作风险极高的受试者到已确诊的RA受试者 在治疗下，2）在与RA相关的自身抗原反应的抗原特异性循环和组织浸润B和T细胞中可鉴定治疗靶点，这需要外周血和滑膜的配对研究，和3）探索滑膜“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，在外周血和滑膜中鉴定，将确定新的途径和相关的疾病目标，驱动炎症，软骨破坏和骨丢失。最后，为了发展超声引导滑膜活检技术的专业知识，利兹大学的Paul Emery教授为美国研究人员制定了“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.