Environmental Factors and Autoantibody Expression in Rheumatoid Arthritis

描述（由申请人提供）： 风湿性关节炎（RA）是世界范围内最常见的炎性关节炎之一。在美国退伍军人中，RA与大量发病率，死亡率加速和治疗费用迅速上升有关。幸运的是，我们最近对RA发病机制的理解有了很大的进展，包括对抗原特异性自身抗体在疾病传播中的作用的了解。来自我们小组和其他人的初步证据表明，选择的自身抗体可能作为疾病进展的强大生物标志物，实际上可能直接介导RA的关节损伤。此外，我们的初步数据表明，RA中的抗原特异性自身抗体反应可能是由环境因素（包括吸烟和牙周炎（PD））“塑造”的，这些因素可以在未来的疾病治疗和/或预防策略中作为目标。现在大量的初步数据支持，我们的总体假设是，环境因素直接影响特定自身抗原的形成和耐受性的损失，在RA，导致适应性免疫反应，反过来又有深远的影响在RA。我们计划检验我们的中心假设，从而通过追求以下三个具体目标来实现本申请的目标：目标1将检查RA中抗原特异性自身抗体应答与放射学疾病进展的相关性。研究最初将使用最近完成的多国VA合作研究项目（CSP）551研究中入组的患者已有的数据和血清样本进行。将在另一个RA队列中重复分析，以减少假阳性结果。这一目标将包括初步研究 探讨选择性自身抗体是否刺激破骨细胞功能和骨吸收，RA骨侵蚀的病理特征。目的2将检查龈下微生物组组成（在PD的背景下改变）与RA风险的关联。这些分析将利用可用的数据和生物样本（包括龈下菌斑样本）作为有史以来最大的病例对照研究的一部分，该研究由PI领导，旨在检查PD与RA风险的相关性。目标3将研究环境因素（吸烟和PD）在多大程度上塑造RA中的自身抗体反应。在这一目标的研究将包括选择龈下细菌是否影响循环T细胞的抗原特异性反应，从而促进RA的全身自身免疫的初步探索。本研究中提出的问题非常重要;解决科学问题和我们目前的理解差距，除了塑造未来的研究议程外，很有可能改变RA在临床管理中的方式。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) represents one of the most common forms of inflammatory arthritis worldwide. Among U.S. Veterans, RA is associated with substantial morbidity, accelerated mortality, and rapidly rising treatment costs. Fortunately, there have been substantial recent gains in our understanding of RA pathogenesis including insight into the role of antigen-specific autoantibodies in disease propagation. Preliminary evidence from our group and others suggest that select autoantibodies may serve as robust biomarkers for disease progression and indeed may actually directly mediate the joint damage that characterizes RA. Moreover, our preliminary data suggests that antigen-specific autoantibody responses in RA may be 'shaped' by environmental factors including cigarette smoking and periodontitis (PD), modifiable factors that could be targeted in future strategies of disease treatment and/or prevention. Supported now by substantial preliminary data, our overarching hypothesis is that environmental factors directly impact the formation of specific autoantigens and tolerance loss in RA, leading to adaptive immune responses that in turn have profound implications in RA. We plan to test our central hypothesis and, thereby, accomplish the objectives of this application by pursuing the following three specific aims: Aim 1 will examine the associations of antigen-specific autoantibody responses in RA with radiographic disease progression. Studies will initially be conducted using data and serum samples already available for patients enrolled in the recently completed multinational VA Cooperative Study Program (CSP) 551 Study. Analyses will be replicated in an additional RA cohort to mitigate false positive findings. This aim will include preliminary studies exploring whether select autoantibodies stimulate osteoclast function and bone resorption, pathologic features of bony erosion in RA. Aim 2 will examine associations of subgingival microbiome composition (altered in the context of PD) with RA risk. These analyses will leverage data and biosamples available (including subgingival bacterial plaque samples) as part of the largest case-control study ever conducted examining the association of PD with RA risk led by the PI. Aim 3 will then examine to what extent environmental factors (both smoking and PD) shape autoantibody responses in RA. Studies in this aim will include initial explorations of whether select subgingival bacteria influence antigen-specific responses of circulating T-cells, thus promoting systemic autoimmunity in RA. The questions proposed in this study are highly significant; addressing scientific questions and current gaps in our understanding that have a high probability of altering the way the RA is approached in clinical management in addition to shaping a future research agenda.