Adipose Inflammation in Rheumatoid Arthritis

 描述（由申请人提供）：肥胖是类风湿性关节炎（RA）发生的既定危险因素，并被认为是近期RA发病率上升的主要原因。然而，脂肪组织对类风湿关节炎疾病状态的免疫学贡献很少得到事先调查。炎症性脂肪组织和炎症性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发挥作用，使细胞活化永久化，产生额外的炎症介质，增加心脏代谢危险因素，并加速动脉粥样硬化形成。除此之外，更高的全身性炎症、胰岛素抵抗和加速动脉粥样硬化的显著倾向是RA的突出特征，表明脂肪炎症在RA疾病过程中的潜在作用。 从初步数据来看，我们观察到RA患者与匹配的对照组相比，脂肪炎症的多项指标水平更高。较高水平的脂肪炎症与RA疾病活动、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定义特征和关键共病后遗症的贡献者。此外，我们观察到强大的关联的频率和炎症基因表达谱的循环中间的“炎症”单核细胞和记忆效应T细胞亚群与RA脂肪组织的炎症特征，表明发炎的脂肪组织和循环免疫效应之间的接口。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）扫描]是否与RA的疾病特征相关尚不清楚。在这方面，我们建议：1.在DMARD反应性与脂肪组织巨噬细胞含量降低和脂肪炎症其他次要指标降低相关的假设下，量化RA患者接受疾病缓解性抗风湿药物（DMARD）治疗时发生的脂肪组织炎症指标的变化。2.描述RA特征性外周血单核细胞（PBMC）亚群（即循环中间单核细胞和/或终末分化记忆/效应T细胞）的免疫表型特征与RA脂肪组织炎症的相关性。3.评估脂肪FDG摄取与脂肪抽吸、RA特征和血管炎症中脂肪组织炎症指标的相关性。这些目标的完成将定义脂肪组织的关键病理生物学特征的RA的独特贡献，建立治疗反应，并确定新的方法进行筛选和预测。

 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.