BACKGROUND Unbiased studies using different genome-wide methods have identified several novel biomarkers for diagnosis and treatment response in Rheumatoid Arthritis (RA). However, clinical translation has proven difficult. Here, we hypothesized that one reason could be that inflammatory responses in peripheral blood are different from those in the arthritic joint. METHODS We performed meta-analysis of gene expression microarray data from synovium, whole blood cells (WBC), peripheral blood mononuclear cells (PBMC), and CD4+ T cells from patients with RA and healthy controls in order to identify overlapping pathways, upstream regulators and potential biomarkers. We also analyzed single cell RNA-sequencing (scRNA-seq) data from peripheral blood and whole joints from a mouse model of antigen-induced arthritis. RESULTS Analyses of two profiling data sets from synovium from RA patients and healthy controls all showed significant activation of pathways with known pathogenic relevance, such as the Th1 pathway, the role of NFAT in regulation of the immune response, dendritic cell maturation, iCOS-iCOSL signaling in T helper cells, Fcγ receptor-mediated phagocytosis, interferon signaling, Cdc42 signaling, and cytotoxic T lymphocyte-mediated apoptosis. The most activated upstream regulators included TNF, an important drug target, as well as IFN-gamma and CD40LG, all of which are known to play important pathogenic roles in RA. The differentially expressed genes from synovium included several potential biomarkers, such as CCL5, CCL13, CCL18, CX3CL1, CXCL6, CXCL9, CXCL10, CXCL13, IL15, IL32, IL1RN, SPP1, and TNFSF11. By contrast, microarray studies of WBC, PBMC and CD4+ T cells showed variable pathways and limited pathway overlap with synovium. Similarly, scRNA-seq data from a mouse model of arthritis did not support that inflammatory responses in peripheral blood reflect those in the arthritic joints. These data showed pathway overlap between mouse joint cells and synovium from patients with RA, but not with cells in peripheral blood. CONCLUSIONS Our findings indicate a dichotomy between gene expression changes, pathways, upstream regulators and biomarkers in synovium and cell types in peripheral blood, which complicates identification of biomarkers in blood.

中文翻译：

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大量和单细胞转录组学数据表明，外周血和关节炎关节炎症通路之间的二分法使生物标志物的发现复杂化

背景 使用不同全基因组方法的无偏见研究已经鉴定了几种用于类风湿性关节炎 (RA) 诊断和治疗反应的新型生物标志物。然而，临床翻译已被证明是困难的。在这里，我们假设一个原因可能是外周血中的炎症反应与关节炎关节中的炎症反应不同。方法 我们对来自 RA 患者和健康对照的滑膜、全血细胞 (WBC)、外周血单核细胞 (PBMC) 和 CD4+ T 细胞的基因表达微阵列数据进行荟萃分析，以识别重叠通路、上游调节因子和潜在的生物标志物。我们还分析了来自抗原诱导关节炎小鼠模型的外周血和整个关节的单细胞 RNA 测序 (scRNA-seq) 数据。结果 对来自 RA 患者和健康对照的滑膜的两个分析数据集的分析均显示具有已知致病相关性的通路的显着激活，例如 Th1 通路、NFAT 在调节免疫反应中的作用、树突细胞成熟、iCOS-iCOSL T 辅助细胞中的信号传导、Fcγ 受体介导的吞噬作用、干扰素信号传导、Cdc42 信号传导和细胞毒性 T 淋巴细胞介导的细胞凋亡。最活跃的上游调节剂包括重要的药物靶点 TNF 以及 IFN-γ 和 CD40LG，已知所有这些都在 RA 中发挥重要的致病作用。来自滑膜的差异表达基因包括几种潜在的生物标志物，例如 CCL5、CCL13、CCL18、CX3CL1、CXCL6、CXCL9、CXCL10、CXCL13、IL15、IL32、IL1RN、SPP1 和 TNFSF11。相比之下，WBC 的微阵列研究，PBMC 和 CD4+ T 细胞显示出不同的通路和有限的通路与滑膜重叠。同样，来自关节炎小鼠模型的 scRNA-seq 数据不支持外周血中的炎症反应反映关节炎关节中的炎症反应。这些数据显示小鼠关节细胞和 RA 患者的滑膜之间的通路重叠，但与外周血中的细胞没有重叠。结论我们的研究结果表明滑膜和外周血细胞类型的基因表达变化、通路、上游调节因子和生物标志物之间存在二分法，这使得血液中生物标志物的鉴定变得复杂。这些数据显示小鼠关节细胞和 RA 患者滑膜之间的通路重叠，但与外周血中的细胞没有重叠。结论我们的研究结果表明滑膜和外周血细胞类型的基因表达变化、通路、上游调节因子和生物标志物之间存在二分法，这使得血液中生物标志物的鉴定变得复杂。这些数据显示小鼠关节细胞和 RA 患者的滑膜之间的通路重叠，但与外周血中的细胞没有重叠。结论我们的研究结果表明滑膜和外周血细胞类型的基因表达变化、通路、上游调节因子和生物标志物之间存在二分法，这使得血液中生物标志物的鉴定变得复杂。