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IL-21 enhances STAT3/Blimp-1 signaling pathway in B cells and contributes to plasma cell differentiation in newly diagnosed patients with myasthenia gravis
Immunologic Research ( IF 3.3 ) Pub Date : 2020-11-03 , DOI: 10.1007/s12026-020-09164-2
Yanan Xu 1, 2 , Xiaoyu Huang 1 , Fengzhan Li 1 , Tan Liu 1 , Tingting Yang 1 , Fei Chen 1, 3 , Jie Zhu 1, 3 , Meng Pan 1, 4 , Yong Zhang 1 , Yuzhong Wang 5 , Linlin Fu 6 , Chenghua Xiao 1 , Deqin Geng 1
Affiliation  

The transcription factor Blimp-1 is necessary for the B cell differentiation toward immunoglobulin-secreting plasma cells. However, the immunopathological mechanisms of Blimp-1 that regulates B cell differentiation remain unclear in MG. The purpose of this study was to perform a quantitative and functional analysis of Blimp-1 in MG. A total of 34 patients with MG (18 ocular MG (OMG) and 16 generalized MG (GMG) and 20 healthy controls (HC) were recruited in this study. CD19+ B cells were isolated by positive selection using CD19 beads. The expression of Blimp-1 and p-STAT3 protein in isolated B cells was assessed by Western blot. Plasma cells were analyzed by flow cytometry. Serum IL-21 levels were detected by ELISA. Our data demonstrated that Blimp-1 in peripheral blood B cell of MG patients was significantly increased compared with HC. The increased expression of Blimp-1 was positively associated with clinical severity score (QMGs), plasma cell frequency, and serum IL-21 levels. Furthermore, glucocorticoid (GC) treatment reduced the expression of Blimp-1 and p-STAT3 in B cells, and this change was accompanied with relieved clinical severity, reduced plasma cell frequency, and decreased serum IL-21 levels. In vitro assay demonstrated that IL-21 stimulation upregulated STAT3 phosphorylation, increased Blimp-1 expression in B cells, and promoted plasma cell differentiation, and these processes could be inhibited by dexamethasone or STAT3 inhibitor stattic. This work indicates for the first time that aberrant expression of Blimp-1 exists on B cells and contributes to the plasma cell differentiation in MG patients. Modulation of IL-21/STAT3/Blimp-1 signaling pathway in B cells may be one of the mechanisms of glucocorticoid in the treatment of MG.



中文翻译:

IL-21 增强 B 细胞中的 STAT3/Blimp-1 信号通路并有助于新诊断重症肌无力患者的浆细胞分化

转录因子 Blimp-1 是 B 细胞向分泌免疫球蛋白的浆细胞分化所必需的。然而,调节 B 细胞分化的 Blimp-1 的免疫病理机制在 MG 中仍不清楚。本研究的目的是对 MG 中的 Blimp-1 进行定量和功能分析。本研究共招募 34 名 MG 患者(18 名眼部 MG (OMG) 和 16 名全身性 MG (GMG) 和 20 名健康对照 (HC))。CD19 +B 细胞通过使用 CD19 珠子的阳性选择来分离。通过蛋白质印迹评估分离的 B 细胞中 Blimp-1 和 p-STAT3 蛋白的表达。通过流式细胞术分析浆细胞。通过ELISA检测血清IL-21水平。我们的数据表明,与HC相比,MG患者外周血B细胞中的Blimp-1显着增加。Blimp-1 表达的增加与临床严重程度评分 (QMG)、浆细胞频率和血清 IL-21 水平呈正相关。此外,糖皮质激素 (GC) 治疗降低了 B 细胞中 Blimp-1 和 p-STAT3 的表达,这种变化伴随着临床严重程度的减轻、浆细胞频率的降低和血清 IL-21 水平的降低。体外试验表明 IL-21 刺激上调 STAT3 磷酸化,B 细胞中 Blimp-1 表达增加,促进浆细胞分化,这些过程可以被地塞米松或 STAT3 抑制剂 stattic 抑制。这项工作首次表明 Blimp-1 的异常表达存在于 B 细胞上,并有助于 MG 患者的浆细胞分化。B细胞中IL-21/STAT3/Blimp-1信号通路的调节可能是糖皮质激素治疗MG的机制之一。

更新日期:2020-11-04
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