Adipose Inflammation in Rheumatoid Arthritis

 描述(由申请人提供)：肥胖是类风湿性关节炎(RA)发展的既定危险因素，并已被认为是最近RA发病率上升的主要来源。然而，脂肪组织对类风湿性关节炎疾病状态的免疫学贡献很少得到先前的研究。炎症脂肪组织和类风湿关节炎滑膜之间的相似之处是惊人的，产生的细胞因子、趋化因子和脂肪因子激素通过旁分泌和内分泌机制来维持细胞激活，阐述额外的炎症介质，增加心脏代谢危险因素，并加速动脉粥样硬化的形成。与此平行的是，更高的全身炎症、胰岛素抵抗和明显的动脉粥样硬化加速倾向是类风湿性关节炎的显著特征，提示脂肪炎症在类风湿性关节炎的发病过程中具有潜在的作用。从初步数据中，我们观察到与匹配的对照组相比，RA患者的多项脂肪炎症指标水平更高。较高的脂肪炎症水平与RA疾病活动性、循环炎症标志物、胰岛素抵抗和动脉粥样硬化密切相关，表明RA脂肪组织是RA的明确特征和关键的共病后遗症的贡献者。此外，我们观察到循环中间“炎症”单核细胞和记忆效应器T细胞亚群的频率和炎症基因表达谱与类风湿关节炎脂肪组织的炎症特征有很强的相关性，表明炎症脂肪组织和循环免疫效应器之间存在界面。然而，这些特征是否可以通过RA药物治疗来改变，以及脂肪炎症的非侵入性测量[如18氟脱氧葡萄糖(FDG)正电子发射断层扫描(PET)]是否与RA的疾病特征相关，目前尚不清楚。在此背景下，我们建议：1.在疾病修饰性抗风湿药物(DMARD)治疗将与脂肪组织巨噬细胞含量的减少和脂肪炎症的其他次要指标的减少相关的假设下，量化RA患者脂肪组织炎症指标的变化。2.探讨类风湿性关节炎患者外周血中单个核细胞亚群(即循环中间单核细胞和/或终末分化的记忆/效应T细胞)的免疫表型特征与脂肪组织炎症的关系。3.评估脂肪摄取FDG与脂肪组织炎症指标、RA特征和血管炎症的相关性。这些目标的完成将确定脂肪组织对RA的关键病理生物学特征的独特贡献，建立治疗反应性，并确定筛查和预测的新方法。

 DESCRIPTION (provided by applicant): Obesity is an established risk factor for the development of rheumatoid arthritis (RA), and has been implicated as the primary source of the recent rise in RA incidence. However, the immunologic contribution of adipose tissue to the RA disease state has received little prior investigation. Parallels between inflamed adipose tissue and the inflamed synovium of RA are striking, and the cytokines, chemokines, and adipokine hormones produced act via paracrine and endocrine mechanisms to perpetuate cellular activation, elaborate additional inflammatory mediators, increase cardiometabolic risk factors, and accelerate atherogenesis. Paralleling this, higher systemic inflammation, insulin resistance, and a marked propensity toward accelerated atherosclerosis are prominent features of RA, suggesting a potential role for adipose inflammation in the RA disease process. From preliminary data, we observed higher levels of multiple measures of adipose inflammation in RA patients compared with matched controls. Higher levels of adipose inflammation were strongly correlated with RA disease activity, circulating inflammatory markers, insulin resistance, and atherosclerosis, suggesting that RA adipose tissue is a contributor to the defining features and key comorbid sequelae of RA. Moreover, we observed robust associations in the frequency and inflammatory gene expression profiles of circulating intermediate "inflammatory" monocytes and memory effector T cell subsets with inflammatory characteristics of RA adipose tissue, suggesting an interface between inflamed adipose tissue and circulating immune effectors. However, whether these features are modifiable with RA pharmacotherapies and whether non-invasive measures of adipose inflammation [such as 18fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning] are correlated with the disease features of RA are unknown. Within this context, we propose to: 1. Quantify the changes in measures of adipose tissue inflammation occurring with disease modifying anti- rheumatic drug (DMARD) therapy in RA patients, under the hypothesis that DMARD responsiveness will be associated with a decrease in adipose tissue macrophage content and decreases in other secondary measures of adipose inflammation. 2. Delineate the associations of the immunophenotypic characteristics of subsets of peripheral blood mononuclear cells (PBMCs) characteristic of RA (i.e. circulating intermediate monocytes and/or terminally differentiated memory/effector T-cells) with adipose tissue inflammation in RA. 3. Evaluate the associations of adipose FDG uptake with measures of adipose tissue inflammation from adipose aspiration, RA characteristics, and vascular inflammation. Completion of these aims will define unique contributions of adipose tissue to the key pathobiologic features of RA, establish treatment responsiveness, and identify novel methods for screening and prediction.