Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
Norwegian Institute for Bioeconomy Research, National Forest Inventory, Ås, Norway.
Front Immunol. 2021 Apr 9;12:663736. doi: 10.3389/fimmu.2021.663736. eCollection 2021.
Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as , and Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.
类风湿关节炎（RA）是一种复杂的疾病，具有广泛的潜在易感因素。最近，在血液中的几种免疫细胞类型中已经报道了 microRNAs（miRNAs）的失调。然而，B 细胞尚未得到详细研究。鉴于 RA 具有自身抗体的自身免疫性质，CD19+B 细胞是 RA 发病机制中的关键细胞类型，并且在患者血液中观察到 CD19+B 细胞亚群的改变。因此，我们旨在揭示血液衍生的 CD19+B 细胞中同种 RA 患者表型的全局 miRNA 谱，并分析 miRNA 表达谱差异。对新诊断未治疗的 RA 患者（n=10）、成功接受甲氨蝶呤（MTX）治疗缓解的 RA 患者（MTX 治疗 RA 患者，n=18）和健康对照者（n=9）的 CD19+B 细胞进行了小 RNA 测序。大多数 miRNA 在所有表型中均有检测到。然而，在 MTX 治疗的 RA 患者和对照组之间观察到 27 个 miRNA 的表达差异显著，而新诊断的患者和对照组之间未见显著差异。一些差异表达的 miRNA 先前在 RA 中被发现失调，包括 miR-223-3p、miR-486-3p 和 miR-23a-3p。使用差异表达的 miRNA 和 miRTarBase 中的 miRNA-靶标相互作用作为输入，对 miRNA 靶标富集分析表明，富集了已知在 B 细胞激活、分化和 B 细胞受体信号传导中发挥重要作用的靶基因，如 、 和 。有趣的是，与其他免疫细胞类型相比，许多这些基因在 CD19+B 细胞中表现出高度相关的表达。我们的结果表明 miRNA 在 MTX 治疗的 RA 患者血液衍生的 CD19+B 细胞中具有重要的调节功能，并为进一步研究 miRNA 和基因靶标之间的相互作用机制以及 miRNA 对 RA 治疗反应的可能预测能力提供了动力。
