The Role of the Lung in the Initiation of Rheumatoid Arthritis

描述（由申请人提供）：类风湿关节炎（RA）是一种全身性自身免疫性疾病，其临床和病理特征为包括关节和肺部在内的多组织损伤。现在已经确定，RA相关自身抗体（Abs）可能在症状性炎症性关节炎（IA）发病前几年在血液中升高，这段无症状自身免疫的时期称为RA的“临床前”阶段。重要的是，这个临床前阶段的长时间表明，引发RA的免疫过程发生在关节外的部位。这个地点目前未知；然而，我们的中心假设是肺是ra相关自身免疫最初产生的部位。这一假设基于多种观察，包括：(i)吸烟等吸入因素与RA风险增加的关联，（ii）我们和其他人发表的研究表明，肺部疾病，特别是气道疾病，是RA的早期甚至表现为RA的表现，（iii）在已确诊RA患者的诱导支气管相关淋巴组织（iBALT）中发现浆细胞产生RA相关抗体（Rangel-Moreno et al . 2006）。（iv）我们发表的研究表明，在没有RA但未来发展为RA的高风险受试者中，气道异常与RA相关的Ab升高之间存在很强的相关性；(v)我们的初步数据使用了一组独特的未来RA高风险受试者的痰液分析，显示RA相关的抗体似乎在肺部产生。该项目的主要目标是确定与ra相关的抗体最初是在肺中产生的，并确定肺中与这种自身免疫产生相关的特定组织变化。次要目的是确定ra相关自身免疫与肺和关节疾病进展之间的关系。我们将利用我们独特的资源，包括未来RA风险受试者的大队列，来实现这些特定目标：1)表征RA自然史期间受试者痰液和血清中RA相关抗体的表型，重点关注RA发展的临床前阶段；2)评估肺组织组织学，以确定RA相关自身免疫发展相关的因素。通过这些目标，我们期望证明ra相关的自身免疫在没有关节炎的情况下在肺中产生，特异性Ab表型与肺和关节疾病的发生和进展相关。包括iBALT的存在在内的肺部特异性免疫变化与这些抗体的产生有关。我们相信这些发现将为进一步研究肺部RA发展的特定机制提供重要支持，最终可以靶向疾病预防。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized clinically and pathologically by injury to multiple tissues including the joints and the lungs. It is now well-established that RA-related autoantibodies (Abs) may be elevated in blood years prior to the onset of symptomatic inflammatory arthritis (IA), with this period of asymptomatic autoimmunity termed the 'preclinical' phase of RA. Importantly, the long duration of this preclinical period suggests that the immunologic processes that initiate RA are occurring at a site outside of the joints. This site is currently unknown; however, our central hypothesis is that lung is the site of initial generation of RA-related autoimmunity. This hypothesis is based on multiple observations including: (i) the association of inhaled factors such as tobacco smoke with increased risk for RA, (ii) published studies by ourselves and others demonstrating that lung disease, and in particular airways disease, is an early or even presenting manifestation of RA, (iii) the identification of plasma cells generating RA-related Abs within inducible bronchus-associated lymphatic tissue (iBALT) from patients with established RA (Rangel-Moreno et al 2006), (iv) our published work demonstrating a strong association between airways abnormalities and RA-related Ab elevations in subjects without RA but who are at high-risk for the future development of RA, and (v) our preliminary data using analyses of sputa in a unique cohort of subjects at high-risk for future RA to show that RA-related Abs appear to be generated in the lung. The primary objectives of this project are to establish that RA-related Abs are initially generated in the lung, and identify specific tissue changes in the lung that are associated with the generation of this autoimmunity. The secondary objective is to determine the relationship between RA-related autoimmunity and the progression of lung and joint disease. We will address these objectives by using our unique resources, including large cohorts of subjects at-risk for future RA, to perform these Specific Aims: 1) to characterize the phenotypes of RA-related Abs in sputa and sera from subjects during the natural history of RA, with a focus on the preclinical period of RA development, and 2) to evaluate the histology of lung tissue to identify factors that are associated the development of RA-related autoimmunity. Through these Aims, we expect to demonstrate that RA-related autoimmunity is generated in the lung in the absence of arthritis, specific Ab phenotypes are associated with the development and progression of lung and joint disease, and that specific immunologic changes in the lung including the presence of iBALT are associated with the generation of these Abs. We believe that these findings will provide important support for further studies of specific mechanisms of development of RA in the lungs that can ultimately be targeted for disease prevention.