Environmental Factors and Autoantibody Expression in Rheumatoid Arthritis

类风湿性关节炎的环境因素和自身抗体表达

• 批准号: 8633136
• 负责人: TED RICHARD MIKULS
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633136
• 关键词: Accounting; Address; Affect; Age; Anaerobic Bacteria; Antibodies; Antigens; Arthritis; Autoantibodies; Autoantigens; Autoimmunity; Bacteria; Biological Assay; Biological Availability; Biological Markers; Bone Resorption; Calcium; Case-Control Studies; Clinical; Clinical Management; Collagen Type II; Complex; Conflict (Psychology); Data; Degenerative polyarthritis; Development; Disease; Disease Progression; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Enzymes; Fibrinogen; Future; General Population; Generations; Healthcare; Immune response; Immune system; Immunity; Infection; Investigation; Lead; Link; Mediating; Morbidity - disease rate; Nature; Osteoclasts; Outcome; Pathogenesis; Patients; Peptides; Periodontitis; Phenotype; Play; Population; Porphyromonas gingivalis; Positioning Attribute; Prevalence; Prevention; Probability; Prokaryotic Cells; Proteins; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sampling; Serum; Shapes; Smoking; Specificity; T cell response; T-Lymphocyte; Testing; Treatment Cost; Veterans; Vimentin; Woman; Work; case control; cigarette smoking; cohort; cooperative study; cost; cyclic citrullinated peptide; disability; disorder prevention; enolase; experience; improved; insight; joint destruction; joint injury; male; men; microbial; microbiome; mortality; novel strategies; oral infection; oral microbiome; outcome forecast; pathologic bone resorption; programs; public health relevance; pyrosequencing; response

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.

类风湿性关节炎 (RA) 是最常见的炎症性关节炎之一 全世界。在美国退伍军人中，RA 与高发病率、加速发病率相关 死亡率和迅速上涨的治疗费用。幸运的是，最近有大量 加深了我们对 RA 发病机制的理解，包括深入了解抗原特异性的作用 疾病传播中的自身抗体。我们小组和其他人的初步证据 表明选择的自身抗体可以作为疾病进展的强有力的生物标志物， 实际上可能直接介导 RA 所特有的关节损伤。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“塑造的” 受环境因素影响，包括吸烟和牙周炎 (PD)、可改变的因素 这可以作为未来疾病治疗和/或预防策略的目标。支持 现在通过大量的初步数据，我们的总体假设是环境因素 直接影响 RA 中特定自身抗原的形成和耐受性丧失，导致 适应性免疫反应反过来对 RA 具有深远的影响。我们计划测试我们的 中心假设，从而通过追求以下目标来实现本应用的目标 以下三个具体目标： 目标 1 将检查抗原特异性的关联 RA 中的自身抗体反应随影像学疾病进展。研究最初将是 使用最近参加的患者已有的数据和血清样本进行 完成了跨国 VA 合作研究计划 (CSP) 551 研究。分析将是 在另一个 RA 队列中进行复制，以减少假阳性结果。这一目标将包括 初步研究探索选择的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。目标 2 将检查以下关联 龈下微生物组组成（在 PD 背景下发生改变）与 RA 风险。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 迄今为止最大的病例对照研究的一部分，该研究检查了 PD 与 RA 的关联 PI 主导的风险。然后目标 3 将检查环境因素（包括吸烟）在多大程度上 和 PD）塑造 RA 中的自身抗体反应。针对这一目标的研究将包括初步 探索选择的龈下细菌是否影响抗原特异性反应 循环 T 细胞，从而促进 RA 中的系统性自身免疫。 本研究提出的问题非常重要；解决科学问题和 目前我们理解上的差距很可能会改变 RA 的方式 除了制定未来的研究议程外，还探讨了临床管理方面的问题。