The Role of the Lung in the Initiation of Rheumatoid Arthritis

描述(申请人提供)：类风湿性关节炎(RA)是一种全身性自身免疫性疾病，临床和病理特征为多组织损伤，包括关节和肺部。现已证实，RA相关自身抗体(Abs)在症状性炎症性关节炎(IA)发病前的几年内可能升高，这一无症状自身免疫期被称为RA的临床前阶段。重要的是，这一临床前期的长期持续表明，启动类风湿关节炎的免疫过程发生在关节外的某个部位。这个部位目前尚不清楚；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。这一假说建立在多个观察的基础上，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，特别是呼吸道疾病，是RA的早期或甚至是表现的表现，(Iii)从确诊的RA患者的可诱导支气管相关淋巴组织(IBALT)中鉴定产生RA相关抗体的浆细胞(Rangle-Moreno等人，2006年)，(Iv)我们发表的工作表明，在没有RA但对RA未来发展具有高风险的受试者中，呼吸道异常与RA相关抗体升高之间存在强烈关联，以及(V)我们使用对未来RA高危受试者独特队列中的痰进行分析的初步数据，表明RA相关抗体似乎是在肺中产生的。该项目的主要目标是确定RA相关抗体最初是在肺中产生的，并确定肺中与这种自身免疫的产生相关的特定组织变化。第二个目标是确定RA相关自身免疫与肺部和关节疾病进展的关系。我们将通过使用我们独特的资源，包括大量未来RA的风险受试者，来实现这些特定目标：1)表征RA自然发展过程中受试者痰和血清中RA相关抗体的表型，重点是RA发展的临床前阶段；2)评估肺组织的组织学，以确定与RA相关自身免疫发展相关的因素。通过这些目标，我们期望证明在没有关节炎的情况下，RA相关的自身免疫在肺中产生，特定的抗体表型与肺部和关节疾病的发生和发展相关，以及肺中的特定免疫变化，包括iBALT的存在，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RA在肺部的具体发展机制提供重要支持，最终可以作为疾病预防的靶点。

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.