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

摘要/概要 类风湿性关节炎（RA）是一种常见的自身免疫性风湿性疾病，目前尚无治愈方法，甚至有新的治疗方法。 治疗，与严重的不可逆的关节损伤，身体残疾，和许多 合并症。血清抗瓜氨酸蛋白抗体（ACPA）的出现表明RA相关 自身免疫性，并定义了RA临床前阶段的开始，这是识别相关免疫性的理想时间。 疾病风险生物标志物和疾病预防方法。RA的病因具有遗传成分， 在疾病发展过程中可能与环境相互作用。RA的特点是过度的慢性 炎症，表明控制/解决炎症的能力失败。两种启动机制 和解决炎症对于生理稳态是重要的。脂质介质， 欧米茄-3和欧米茄-6多不饱和脂肪酸的代谢参与启动和消退 炎症。我们已经表明，一个单独的欧米茄-6脂质介质（5-HETE）水平升高， 从RA相关自身免疫性进展为炎性关节炎的风险增加。然而，作为脂质 介质共享共同的途径和酶，我们建议，个别脂质介质不起作用， 隔离，因此应作为一个概况进行组合分析。我们建议分三个阶段进行研究 新的高危人群：预防风湿性关节炎的靶向免疫应答（TIP-RA）人群 81名ACPA+个体，79名ACPA+个体的RA病因学研究（SERA）队列，以及 StopRA队列，包括144名处于RA临床前阶段的ACPA+个体，随时间推移进行了以下随访： RA的发展。我们将创建脂质介体概况（高度相关性的组合的综合评分）。 相关的脂质介质），表明通过执行主成分来解决炎症的能力 分析脂质介质，并观察这些曲线随时间的变化轨迹。目标1将决定 这些特征与从ACPA+进展为RA的相关性因RA的遗传易感性而异。我们将 还探讨了这种关联是否由细胞因子谱或轨迹介导。目标2将探讨 通过检查脂质介质谱是否与DNA甲基化相关的潜在机制 差异或轨迹。目的3将通过鉴定痰液脂质来检查肺部炎症的消退 与RA相关自身免疫进展为RA相关的介质谱和细胞因子。结果 这项工作将为设计预防研究提供基础， 介质在临床前RA的炎症消退中起作用。无法解决炎症可能导致 慢性炎症; RA的常见致病因素。阐明机制以及网站（即 肺）的炎症消退在RA的临床前阶段显着有助于 了解RA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.