Environmental Factors and Autoantibody Expression in Rheumatoid Arthritis

类风湿性关节炎（RA）是炎性关节炎最常见的形式之一 国际吧在美国退伍军人中，类风湿关节炎与大量发病率相关， 死亡率和治疗费用迅速上升。幸运的是，最近有大量的 我们对RA发病机制的理解，包括对抗原特异性 自身抗体在疾病传播中的作用我们小组和其他人的初步证据 表明选择自身抗体可以作为疾病进展的可靠生物标志物， 实际上可能直接介导了类风湿关节炎的关节损伤。而且我们 初步数据表明，RA中的抗原特异性自身抗体反应可能是“成形的”， 环境因素包括吸烟和牙周炎（PD），可改变的因素 这可能是未来疾病治疗和/或预防战略的目标。支持 根据大量的初步数据，我们的总体假设是， 直接影响RA中特异性自身抗原的形成和耐受性丧失， 适应性免疫反应，这反过来又对RA有深远的影响。我们计划测试 中心假设，从而通过追求 以下三个具体目标：目标1将检查抗原特异性 放射学疾病进展的RA中的自身抗体应答。研究将首先 使用最近入组的患者的数据和血清样本进行 完成多国VA合作研究计划（CSP）551研究。分析将 在另一个RA队列中重复，以减轻假阳性结果。这一目标将包括 探索选择的自身抗体是否刺激破骨细胞功能的初步研究， 骨吸收、骨侵蚀的病理特征。目标2将研究 龈下微生物组组成（在PD的背景下改变）与RA风险。这些分析 将利用现有数据和生物样本（包括龈下菌斑样本）， 有史以来最大规模的病例对照研究的一部分， 由PI领导的风险。目标3将研究环境因素（包括吸烟和 和PD）形成RA中的自身抗体应答。这方面的研究将包括初步的 选择龈下细菌是否影响抗原特异性反应的探索 循环T细胞，从而促进RA中的全身性自身免疫。 这项研究提出的问题是非常重要的;解决科学问题， 我们目前的理解差距，有很大的可能改变RA的方式， 除了塑造未来的研究议程外，还在临床管理中采用了这种方法。

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.