The roles and mechanisms of inflammation resolution in the development of Rheumatoid Arthritis

摘要/摘要 类风湿性关节炎(RA)是一种常见的自身免疫性风湿性疾病，目前还没有治愈的方法，甚至有新的 治疗，与严重的不可逆转的关节损伤、身体残疾和许多 合并症。血清抗瓜氨酸蛋白抗体(ACPA)的出现提示RA相关 自身免疫，并定义了RA临床前阶段的开始，这是识别相关 疾病风险生物标志物和疾病预防方法。类风湿性关节炎的病因有遗传成分， 在疾病的发展过程中可能与环境相互作用。类风湿关节炎的特点是过度慢性 炎症，表明控制/化解炎症的能力失败。这两种启动机制 消炎对生理动态平衡很重要。脂类介体，其产品 Omega-3和omega-6多不饱和脂肪酸的代谢参与启动和分解。 发炎的症状。我们已经证明，个体omega-6脂质介体(5-HETE)水平升高 增加了从RA相关自身免疫进展到炎症性关节炎的风险。然而，作为脂质， 介体共有共同的途径和酶，我们认为个别脂类介体不起作用。 隔离，因此应作为配置文件进行组合分析。我们建议在三年内进行一项研究 新的高危队列：用于预防类风湿性关节炎(TIP-RA)的靶向免疫反应队列 在81例ACPA+患者中，79例ACPA+患者的RA(血清)病因学研究，以及 在RA的临床前阶段，对144名ACPA+患者进行了长期随访的StopRA队列研究 类风湿性关节炎的发展。我们将创建脂质介体配置文件(高度组合的综合分数 相关的脂质介体)表明通过执行主成分来消解炎症的能力 分析脂质介体，并观察这些曲线随时间的轨迹。目标1将决定是否 这些特征与从ACPA+进展到RA的关联因RA的遗传易感性而不同。我们会 还要探索这种关联是否受细胞因子分布或轨迹的影响。Aim 2将探索 通过检查脂质介体特征是否与DNA甲基化相关来揭示其潜在机制 差异或轨迹。目标3将通过识别痰中的脂肪来检查肺部的炎症消退 与类风湿性关节炎相关自身免疫向类风湿性关节炎进展相关的介体类型和细胞因子。结果来自 这项工作将为通过阐明脂质的哪些组合来设计预防研究提供基础 在临床前类风湿关节炎的炎症消退中，介质起着重要作用。无法消解炎症可能会导致 慢性炎症；类风湿性关节炎的常见致病因素。阐明机制以及站点(即 在RA临床前阶段的炎症消退显著有助于 了解类风湿性关节炎的发病机制和创新干预措施的发展。

Abstract/Summary Rheumatoid arthritis (RA), a common autoimmune rheumatic condition, has no cure and even with novel treatments, is associated with significant irreversible joint damage, physical disability, and numerous comorbidities. The appearance of serum anti-citrullinated protein antibodies (ACPAs) indicates RA-related autoimmunity and defines the start of the preclinical period of RA, which is the ideal time to identify relevant disease risk biomarkers and approaches for disease prevention. The etiology of RA has a genetic component, which may interact with environment in the development of disease. RA is characterized by excessive chronic inflammation, suggesting a failure in the ability to control/resolve inflammation. Mechanisms for both initiating and resolving inflammation are important for physiological homeostasis. Lipid mediators, products of the metabolism of omega-3 and omega-6 polyunsaturated fatty acids, are involved in both initiation and resolution of inflammation. We have shown that an elevated level of an individual omega-6 lipid mediator (5-HETE) increased risk of progression from RA-related autoimmunity to inflammatory arthritis. However, as lipid mediators share common pathways and enzymes, we propose that individual lipid mediators do not act in isolation and therefore should be analyzed in combination as a profile. We propose to conduct a study in three novel at-risk cohorts: the Targeting Immune Responses for Prevention of Rheumatoid Arthritis (TIP-RA) cohort of 81 ACPA+ individuals, the Studies of the Etiologies of RA (SERA) cohort of 79 ACPA+ individuals, and the StopRA cohort of 144 ACPA+ individuals in the preclinical period of RA that have been followed over time for the development of RA. We will create lipid mediator profiles (a composite score of combinations of highly correlated lipid mediators) indicating the ability to resolve inflammation by performing principal components analysis of the lipid mediators and look at the trajectories of these profiles over time. Aim 1 will determine if the association of these profiles with progression from ACPA+ to RA differs by genetic susceptibility to RA. We will also explore whether the association is mediated by cytokine profiles or trajectories. Aim 2 will explore the underlying mechanism by examining whether the lipid mediator profiles are associated with DNA methylation differences or trajectories. Aim 3 will examine inflammation resolution in the lung by identifying sputum lipid mediator profiles and cytokines associated with progression from RA-related autoimmunity to RA. Results from this work will provide the foundation for designing prevention studies by elucidating which combinations of lipid mediators play a role in inflammation resolution in preclinical RA. The inability to resolve inflammation can lead to chronic inflammation; a common pathogenic element of RA. Elucidating mechanisms as well as the site (ie lung) of inflammation resolution during the preclinical period of RA significantly contributes to the understanding of pathogenesis and development of innovative interventions for RA.