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: 9232974
• 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/9232974
• 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; Diagnostic radiologic examination; Disease; Disease Progression; Enrollment; Environment; Environmental Exposure; Environmental Impact; Environmental Risk Factor; Enzymes; Etiology; Fibrinogen; Future; General Population; Generations; Healthcare; Immune response; Immune system; Immunity; Infection; Inflammatory Arthritis; Investigation; Link; Mediating; Morbidity - disease rate; Nature; Osteoclasts; Outcome; Pathogenesis; Pathogenicity; Pathologic; Patients; Peptides; Periodontitis; Phenotype; Play; Population; Porphyromonas gingivalis; Positioning Attribute; Prevalence; Prevention; Probability; Prokaryotic Cells; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sampling; Serum; Shapes; Smoking; Specificity; T cell response; T-Lymphocyte; Testing; Treatment Cost; Veterans; Vimentin; Woman; Work; adaptive immune response; case control; cigarette smoking; citrullinated protein; 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; programs; public health relevance; pyrosequencing; response

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.

描述（由申请人提供）： 类风湿性关节炎（RA）是全世界最常见的炎症性关节炎之一。在美国退伍军人中，类风湿性关节炎与高发病率、加速死亡率和迅速上升的治疗费用有关。幸运的是，最近我们对 RA 发病机制的理解取得了实质性进展，包括深入了解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以 RA 为特征的关节损伤。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“塑造”的，包括吸烟和牙周炎 (PD)，这些可改变的因素可以作为未来疾病治疗和/或预防策略的目标。现在得到大量初步数据的支持，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，从而导致适应性免疫反应，进而对 RA 产生深远的影响。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反应与放射学疾病进展的关联。研究最初将使用最近完成的跨国 VA 合作研究计划 (CSP) 551 研究中登记的患者已有的数据和血清样本进行。分析将在额外的 RA 队列中重复，以减少误报结果。该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 将检查龈下微生物组组成（在 PD 背景下发生改变）与 RA 风险的关联。这些分析将利用现有的数据和生物样本（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，研究 PD 与 RA 风险之间的关联。然后，目标 3 将检查环境因素（吸烟和 PD）在多大程度上影响 RA 中的自身抗体反应。这一目标的研究将包括初步探索特定的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；解决科学问题和当前我们理解中的差距，除了制定未来的研究议程外，这些问题很可能会改变 RA 在临床管理中的处理方式。

项目成果

The Link Between Periodontitis and Rheumatoid Arthritis: A Periodontist's Perspective.

• DOI: 10.1007/s40496-014-0040-9
• 发表时间: 2015
• 期刊: Current oral health reports

Utilization of Care Outside the Veterans Affairs Health Care System by US Veterans With Rheumatoid Arthritis.

• DOI: 10.1002/acr.23088
• 发表时间: 2017-06
• 期刊: Arthritis care & research
• 影响因子: 4.7
• 作者: Schwab P;Sayles H;Bergman D;Cannon GW;Michaud K;Mikuls TR;Barton J
• 通讯作者: Barton J

Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis.

• DOI: 10.1002/art.38348
• 发表时间: 2014-05
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: Mikuls, Ted R.;Payne, Jeffrey B.;Yu, Fang;Thiele, Geoffrey M.;Reynolds, Richard J.;Cannon, Grant W.;Markt, Jeffrey;McGowan, David;Kerr, Gail S.;Redman, Robert S.;Reimold, Andreas;Griffiths, Garth;Beatty, Mark;Gonzalez, Shawneen M.;Bergman, Debra A.;Hamilton, Bartlett C., III;Erickson, Alan R.;Sokolove, Jeremy;Robinson, William H.;Walker, Clay;Chandad, Fatiha;O'Dell, James R.
• 通讯作者: O'Dell, James R.