Objectives Though interstitial lung disease (ILD) contributes to excess morbidity and mortality in rheumatoid arthritis (RA), RA-ILD pathogenesis remains incompletely defined. As intermediate, non-classical and suppressed CD14+ monocytes are expanded in RA-ILD, this study sought to characterize gene expression profiles of circulating monocytes in RA-ILD. Methods Peripheral blood mononuclear cells were collected from patients with RA without lung disease (N = 5), RA-ILD (N = 5), idiopathic pulmonary fibrosis (IPF; N = 5), and controls without lung and autoimmune disease (N = 4). RNA was extracted from CD14+ isolated monocytes and subjected to transcriptional analysis of 1365 genes. Gene enrichment and pathway analyses were performed. Results Unsupervised clustering grouped patients with RA-ILD together with IPF for myeloid innate genes. For fibrosis genes, patients with RA-ILD clustered independent of comparator groups. There were 103, 66, and 64 upregulated and 66, 14, and 25 downregulated genes for RA-ILD, RA, and IPF, vs controls, respectively. For RA-ILD, there was increased expression of genes involved in regulating inflammation and fibrosis (SOCS3, CECAM1, LTB4R2, CLEC7A, IRF7, PHYKPL, GBP5, RAPGEF), epigenetic modification (KDM5D, KMT2D, OGT), and macrophage activation. Top canonical pathways included macrophage differentiation-activation, IL-12, neuroinflammatory, glucocorticoid receptor, and IL-27 signalling. Conclusions Circulating monocytes in RA-ILD patients demonstrate unique gene expression profiles with innate immune gene features more aligned with IPF as opposed to RA in the absence of clinical lung disease with fibrosis gene expression that was distinct from RA and IPF. These studies are important for understanding disease pathogenesis and may provide information for future therapeutic targets in RA-ILD.

中文翻译：

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类风湿性关节炎相关间质性肺病中外周血单核细胞的独特转录组学特征


目的 尽管间质性肺病 （ILD） 导致类风湿性关节炎 （RA） 的发病率和死亡率过高，但 RA-ILD 的发病机制仍未完全明确。随着中间、非经典和抑制的 CD14 + 单核细胞在 RA-ILD 中扩增，本研究试图表征 RA-ILD 中循环单核细胞的基因表达谱。方法 从无肺部疾病 （N = 5） 、 RA-ILD （N = 5） 、特发性肺纤维化 （IPF;N = 5），以及无肺和自身免疫性疾病的对照 （N = 4）。从 CD14 + 分离的单核细胞中提取 RNA，并对 1365 个基因进行转录分析。进行基因富集和通路分析。结果 无监督聚类将 RA-ILD 患者与 IPF 一起归为髓系先天基因。对于纤维化基因，RA-ILD 患者独立于对照组聚集。与对照相比，RA-ILD 、 RA 和 IPF 分别有 103 个、 66 和 64 个上调基因，66 、 14 和 25 个基因下调。对于 RA-ILD，参与调节炎症和纤维化的基因 （SOCS3 、 CECAM1 、 LTB4R2 、 CLEC7A、IRF7 、 PHYKPL 、 GBP5 、 RAPGEF ）、表观遗传修饰 （KDM5D 、 KMT2D 、 OGT ）和巨噬细胞活化的基因表达增加。主要典型途径包括巨噬细胞分化激活、 IL-12、神经炎症、糖皮质激素受体和 IL-27 信号传导。结论 RA-ILD 患者的循环单核细胞表现出独特的基因表达谱，在无临床肺部疾病且纤维化基因表达不同于 RA 和 IPF 的情况下，先天免疫基因特征与 IPF 更一致，而不是 RA。 这些研究对于了解疾病发病机制非常重要，并可能为 RA-ILD 的未来治疗靶点提供信息。