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The Role of the Lung in the Initiation of Rheumatoid Arthritis

肺在类风湿关节炎发生中的作用

基本信息

批准号：
8707107
负责人：
Kevin Deane
金额：
$ 39.8万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2014-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：类风湿性关节炎（RA）是一种全身性自身免疫性疾病，其临床和病理特征为包括关节和肺部在内的多个组织损伤。现在已经确定，在有症状的炎症性关节炎 (IA) 发病前数年，血液中与 RA 相关的自身抗体 (Abs) 可能会升高，这一无症状自身免疫期被称为 RA 的“临床前”阶段。重要的是，这个临床前阶段的持续时间较长表明引发 RA 的免疫过程发生在关节外的部位。该网站目前未知；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。这一假设基于多项观察结果，包括：（i）烟草烟雾等吸入因素与 RA 风险增加之间的关联，（ii）我们自己和其他人发表的研究表明，肺部疾病，特别是气道疾病，是 RA 的早期甚至呈现症状，（iii）在可诱导支气管相关淋巴组织（iBALT）中鉴定出产生 RA 相关抗体的浆细胞已确诊的 RA 患者（Rangel-Moreno 等，2006），（iv）我们发表的研究表明，在没有 RA 但未来发展为 RA 高风险的受试者中，气道异常与 RA 相关抗体升高之间存在密切关联，（v）我们使用未来 RA 高风险受试者的独特队列中的痰分析进行初步数据显示，RA 相关抗体似乎是在肺。该项目的主要目标是确定 RA 相关抗体最初是在肺部产生的，并确定肺部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 相关自身免疫与肺和关节疾病进展之间的关系。我们将通过利用我们独特的资源（包括大量有未来 RA 风险的受试者）来实现这些具体目标：1）表征 RA 自然史期间受试者痰和血清中 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，我们希望证明在没有关节炎的情况下，肺部会产生与 RA 相关的自身免疫，特定的抗体表型与肺部和关节疾病的发生和进展有关，并且肺部的特定免疫变化（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肺部 RA 发展的具体机制提供重要支持，最终可用于疾病预防。