First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
Department of Hematology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Rheumatology (Oxford). 2021 Nov 3;60(11):5452-5462. doi: 10.1093/rheumatology/keab229.
B cells play an important pathological role in RA. In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA.
Peripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms.
Higher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared with the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression.
mTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells.
B 细胞在 RA 中起着重要的病理作用。在这项研究中，我们研究了代谢调节剂 mTOR 在 B 细胞中的作用及其与 RA 病理学的相关性。
从 31 名正常受试者和 86 名 RA 患者中分离外周血单核细胞，并评估门控 B 细胞中 mTOR 磷酸化和趋化因子受体表达情况。对来自对照和 RA 患者的外周血 B 细胞进行体外研究，以探讨分子机制。
与对照组相比，RA 患者外周血中 CXCL10（CXCR3 配体）浓度较高，CXCR3+记忆 B 细胞比例较低。CXCL10 浓度较高的 RA 患者 CXCR3+记忆 B 细胞比例较小，疾病活动度较高。用 TNF 抑制剂治疗 1 年可增加 CXCR3+记忆 B 细胞的比例，并降低血清 CXCL10 浓度。与对照组相比，RA 患者 B 细胞中的 mTOR 磷酸化进一步增强，并且在 CXCR3+记忆 B 细胞中选择性增强。CXCR3+记忆 B 细胞中的 mTOR 磷酸化与疾病活动度相关。体外，B 细胞中的 mTOR 磷酸化增强了 IL-6 的产生并增加了 RANKL 的表达。
RA 患者 CXCR3+记忆 B 细胞中 mTOR 的激活与疾病活动度相关，这是通过 IL-6 产生和 RANKL 表达介导的。研究结果还表明，TNF 抑制剂对 CXCL10 与 mTOR 激活的 CXCR3+记忆 B 细胞之间的关联产生影响。
