Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.
Front Immunol. 2018 Oct 11;9:2351. doi: 10.3389/fimmu.2018.02351. eCollection 2018.
B-cell activation is pivotal in rheumatoid arthritis (RA) pathogenesis and represents a relevant therapeutic target. The main aim of this study was to characterize the profiles of B-cell factors and their decoy receptors in RA and evaluate their clinical relevance. sBLyS, sAPRIL, sBCMA, sTACI, sBLyS-R, and several cytokines' serum levels were measured by immunoassays in 104 RA patients and 33 healthy controls (HC). An additional group of 42 systemic lupus erythematosus (SLE) patients were enrolled as disease controls. Whole blood IFI44, IFI44L, IFI6, and MX1 gene expression was measured and averaged into an IFN-score. BLyS membrane expression (mBLyS) was assessed on blood cell subsets by flow cytometry. increased sAPRIL and sBCMA levels were found in RA, whereas BLyS was elevated in very early RA (VERA). No differences were observed for sTACI and sBLyS-R. An increased sBLyS/sBLyS-R ratio was associated with poor clinical outcome at 6 and 12 months in VERA, whereas a positive association with disease activity was observed in established disease. Increased mBLyS expression was found on monocytes, mDCs, neutrophils and B-cells in RA, to a similar extent that in SLE patients. Cluster analysis identified a specific B-cell factors profile overrepresented in RA and associated with autoantibodies, elevated proinflammatory cytokines (IFNα, MIP1α, TNFα, IL-37, and GM-CSF) and increased type-I IFN signature. Increasing sBCMA and sBLyS serum levels upon treatment and mBLyS expression at baseline on monocytes and mDCs, but not B-cells, were associated with poor clinical outcome upon TNFα-blockade. profound and complex alterations of soluble and membrane-bound B-cell factors are observed in RA associated with clinical outcomes, thus supporting its applicability to guide patient stratification along disease course.
B 细胞激活在类风湿关节炎（RA）发病机制中起着关键作用，是一个相关的治疗靶点。本研究的主要目的是描述 RA 患者中 B 细胞因子及其诱饵受体的特征，并评估其临床相关性。采用免疫分析法检测 104 例 RA 患者和 33 例健康对照者（HC）的 sBLyS、sAPRIL、sBCMA、sTACI、sBLyS-R 和几种细胞因子的血清水平。还招募了 42 例系统性红斑狼疮（SLE）患者作为疾病对照。通过流式细胞术检测全血 IFI44、IFI44L、IFI6 和 MX1 基因的表达，并将其平均为 IFN 评分。通过流式细胞术评估血液细胞亚群上的 BLyS 膜表达（mBLyS）。在 RA 患者中发现 sAPRIL 和 sBCMA 水平升高，而在早期 RA（VERA）中 BLyS 升高。sTACI 和 sBLyS-R 无差异。在 VERA 中，sBLyS/sBLyS-R 比值增加与 6 个月和 12 个月时的临床预后不良相关，而在确诊疾病中观察到与疾病活动度的正相关。在 RA 患者中发现单核细胞、mDCs、中性粒细胞和 B 细胞上的 mBLyS 表达增加，与 SLE 患者相似。聚类分析确定了 RA 中特异性 B 细胞因子谱，该谱与自身抗体、促炎细胞因子（IFNα、MIP1α、TNFα、IL-37 和 GM-CSF）升高和 I 型 IFN 特征增加有关。治疗后血清 sBCMA 和 sBLyS 水平升高以及基线时单核细胞和 mDCs 上的 mBLyS 表达（但 B 细胞上无）与 TNFα 阻断后的临床结局不良相关。RA 患者可溶性和膜结合 B 细胞因子发生深刻而复杂的改变，与临床结局相关，因此支持其在指导疾病过程中的患者分层中的应用。
