Shimojima Yasuhiro, Kishida Dai, Ichikawa Takanori, Sekijima Yoshiki
Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
Front Immunol. 2025 Jun 4;16:1586158. doi: 10.3389/fimmu.2025.1586158. eCollection 2025.
Increased expression of B-cell activation factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) expression, which have been observed not only in the active phase of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) but also in remission, may cause relapse by activating autoreactive B cells that produce ANCA. It is necessary to identify a therapeutic target related to the production of BAFF and APRIL in immune cells, particularly monocytes which play a crucial role in mediating the pathological processes of AAV. We previously demonstrated the efficacy of resveratrol (RVL) in restoring the function of regulatory T cells in AAV. This study examined the effects of RVL on the expression of BAFF and APRIL in monocytes as well as their related signaling factors in patients with AAV. This study used peripheral blood mononuclear cells (PBMCs) from 35 patients with AAV and 22 healthy controls. After incubating PBMCs with and without RVL or tempol, BAFF, APRIL, reactive oxygen species (ROS), and nuclear factor-κB (NF-κB) in CD14+ cells were analyzed using flow cytometry. Additionally, BAFF and APRIL in CD14+ cells were assessed in PBMCs treated with the NF-κB inhibitor, SN50. Significantly higher BAFF, APRIL, ROS, and NF-κB expression were observed in CD14+ cells in patients with AAV than in healthy controls. In CD14+ cells treated with RVL, patients with AAV exhibited significant increases in BAFF and NF-κB expression but significant decreases in APRIL and ROS expression. In patients with AAV, there was a positive correlation between NF-κB and BAFF in CD14+ cells, regardless of RVL treatment. Patients with AAV showed a significant decrease in APRIL expression without significant changes in BAFF expression in CD14+ cells treated with tempol; whereas there was a significant decrease in BAFF and APRIL expression in CD14+ cells treated with SN50. NF-κB may be a crucial signaling factor in BAFF production. RVL induces BAFF expression in monocytes by stimulating NF-κB in AAV, while its redox reaction reduces APRIL expression.
肿瘤坏死因子家族的B细胞活化因子（BAFF）和增殖诱导配体（APRIL）表达增加，这不仅在抗中性粒细胞胞浆抗体（ANCA）相关血管炎（AAV）的活动期被观察到，在缓解期也有发现，它们可能通过激活产生ANCA的自身反应性B细胞而导致复发。有必要确定与免疫细胞中BAFF和APRIL产生相关的治疗靶点，尤其是在介导AAV病理过程中起关键作用的单核细胞。我们之前证明了白藜芦醇（RVL）在恢复AAV中调节性T细胞功能方面的疗效。本研究检测了RVL对AAV患者单核细胞中BAFF和APRIL表达及其相关信号因子的影响。本研究使用了35例AAV患者和22名健康对照者的外周血单个核细胞（PBMC）。在用或不用RVL或Tempol孵育PBMC后，使用流式细胞术分析CD14+细胞中的BAFF、APRIL、活性氧（ROS）和核因子κB（NF-κB）。此外，在用NF-κB抑制剂SN50处理的PBMC中评估CD14+细胞中的BAFF和APRIL。与健康对照相比，AAV患者CD14+细胞中BAFF、APRIL、ROS和NF-κB的表达明显更高。在用RVL处理的CD14+细胞中，AAV患者的BAFF和NF-κB表达显著增加，但APRIL和ROS表达显著降低。在AAV患者中，无论是否进行RVL治疗，CD14+细胞中的NF-κB和BAFF之间均呈正相关。在用Tempol处理的CD14+细胞中，AAV患者的APRIL表达显著降低，而BAFF表达无显著变化；而在用SN50处理的CD14+细胞中，BAFF和APRIL表达均显著降低。NF-κB可能是BAFF产生中的关键信号因子。RVL通过刺激AAV中的NF-κB诱导单核细胞中BAFF的表达，而其氧化还原反应降低了APRIL的表达。
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