Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis.
Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis.
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活化的 mTOR 在类风湿性关节炎 CXCR3 记忆 B 细胞中的病理作用。
DOI：
10.1093/rheumatology/keab229
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Tanaka Y.
中科院分区：
文献类型：
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作者：
Iwata S;Zhang M;Hajime M;Ohkubo N;Sonomoto K;Torimoto K;Kitanaga Y;Trimova G;Todoroki Y;Miyata H;Ueno M;Nagayasu A;Kanda R;Nakano K;Nakayamada S;Sakata K;Tanaka Y.
目的探讨b细胞在RA发病中的重要病理作用。在这项研究中，我们研究了代谢调节因子mTOR在B细胞中的作用及其与RA病理的相关性。方法分离31例正常人和86例RA患者外周血单个核细胞，检测门控B细胞mTOR磷酸化水平和趋化因子受体表达水平。通过对对照组和RA患者外周血B细胞的体外研究，探讨了其分子机制。结果与对照组相比，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。高CXCL10浓度的RA患者CXCR3+记忆B细胞百分比较小，疾病活动性高。用TNF抑制剂治疗一年增加了CXCR3+记忆B细胞的百分比，降低了血清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mTOR磷酸化与疾病活性相关。在体外，B细胞中mTOR的磷酸化增强了IL-6的产生并增加了RANKL的表达。结论RA患者CXCR3+记忆B细胞中mtor的激活与疾病活动性相关，通过IL-6的产生和RANKL的表达介导。获得的结果还表明，TNF抑制剂介导CXCL10和mTOR激活的CXCR3+记忆B细胞之间的关联。
ObjectivesB 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.MethodsPeripheral 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 vitrostudies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms.ResultsHigher 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.ConclusionmTOR 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.