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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

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Abstract

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.

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Funding

This work was supported by the Fifth Phase “333 Project” Scientific Research Subsidy Project in Jiangsu Province (BRA2018395), the National Nature Science Foundation of China (81072465, 81571579), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX20_0928), the Innovation and Entrepreneurship Training Program for College Students in Jiangsu Province (201610313038Y), the Key Medical Talents Fund of Jiangsu Province (H201130), and the Jiangsu Province Ordinary University Postgraduate Research Innovation Fund (CXLX11_0734).

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  1. Yanan Xu, Xiaoyu Huang and Fengzhan Li contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Affiliated Hospital of Xuzhou Medical University, No. 99 Huaihai West Road, Quanshan District, Xuzhou, Jiangsu, China

    Yanan Xu, Xiaoyu Huang, Fengzhan Li, Tan Liu, Tingting Yang, Fei Chen, Jie Zhu, Meng Pan, Yong Zhang, Chenghua Xiao & Deqin Geng

  2. Department of Neurology, Nanjing Jiangbei People’s Hospital, No. 552 Geguan Road, Jiangbei New District, Nanjing, Jiangsu, China

    Yanan Xu

  3. Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, 32 Coal Construction Road, Quanshan District, Xuzhou, Jiangsu, China

    Fei Chen & Jie Zhu

  4. Department of Neurology, Nanjing Brain Hospital Affiliated to Nanjing Medical University, 264 Guangzhou Road, Gulou District, Nanjing, Jiangsu, China

    Meng Pan

  5. Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China

    Yuzhong Wang

  6. Department of Pathogenic Biology and Lab of Infection and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Linlin Fu

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  1. Yanan Xu
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Xu, Y., Huang, X., Li, F. et al. IL-21 enhances STAT3/Blimp-1 signaling pathway in B cells and contributes to plasma cell differentiation in newly diagnosed patients with myasthenia gravis. Immunol Res 69, 59–70 (2021). https://doi.org/10.1007/s12026-020-09164-2

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