CXCL12/CXCR4 axis drives the chemotaxis and differentiation of B cells in bullous pemphigoid.
CXCL12/CXCR4 axis drives the chemotaxis and differentiation of B cells in bullous pemphigoid.
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CXCL12/CXCR4轴驱动大疱性类天疱疮中B细胞的趋化和分化。
DOI：
10.1016/j.jid.2022.08.041
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发表时间：
2022-09
期刊：
影响因子：
--
通讯作者：
Gang Wang
中科院分区：
文献类型：
--
作者：
Hui Fang;Ke Xue;Tianyu Cao;Qingyang Li;Erle Dang;Yanghe Liu;Jieyu Zhang;Pei Qiao;Jiaoling Chen;Jingyi Ma;Shengxian Shen;Bingyu Pang;Yaxing Bai;Hongjiang Qiao;Shuai Shao;Gang Wang
大疱性类天疱疮(BP)是一种自身免疫性大疱性皮肤病，其特征是皮肤和粘膜中抗半桥粒蛋白的自身抗体。B细胞靶向生物制剂在BP中的有效性表明B细胞在BP的发病机制中起着重要作用。然而，BP中B细胞的异常迁移和分化尚需进一步阐明。我们发现BP患者循环和皮损中的抗体分泌细胞(ASCs)数量增加，并与疾病严重程度相关。外周血B细胞的批量RNA测序发现，与健康对照组相比，BP患者中有171个基因上调，408个基因下调，其中CXCR4显著上调。值得注意的是，CXCR4+B细胞在BP皮损中丰富，并表现出ASC特征。相应地，BP患者疱液和血清中CXCR4配体CXCL12水平升高，介导CXCR4+B细胞对BP皮损的趋化和聚集。此外，CXCL12激活转录因子c-Myc，从而促进B细胞分化为ASCs，并促进自身抗体的产生，这一作用在体外被CXCR4抑制剂阻断。总之，我们的研究表明，CXCL12/CXCR4轴在调节B细胞的运输和分化方面发挥了致病作用，因此靶向CXCR4是治疗BP和其他自身免疫性疾病的潜在策略。
Bullous pemphigoid (BP) is an autoimmune bullous skin disease characterized by autoantibodies against the hemidesmosomal proteins in the skin and mucous membranes. The efficiency of B cell-targeting biologics in BP indicates the important role of B cells in its pathogenesis. However, abnormal B cell migration and differentiation in BP requires further elucidation. We showed that the number of antibody secreting cells (ASCs) increased in the circulation and skin lesions of BP patients and was correlated with disease severity. Bulk RNA-sequencing of the peripheral B cells identified 171 upregulated and 408 downregulated genes in BP patients compared to healthy controls, among which CXCR4 was significantly upregulated. Notably, CXCR4+ B cells were enriched in BP skin lesions and exhibited ASC characteristics. Correspondingly, elevated level of CXCL12, the CXCR4 ligand, was detected in the blister fluid and serum of BP patients, mediating the chemotaxis and accumulation of CXCR4+ B cells to BP skin lesions. Moreover, CXCL12 activated the transcription factor c-Myc, thus promoting B cell differentiation into ASCs and facilitating autoantibody production, which was blocked by CXCR4 inhibitor in vitro. Collectively, our study reveals that the CXCL12/CXCR4 axis plays a pathogenic role in modulating B cell trafficking and differentiation, thus targeting CXCR4 represents a potential strategy for treating BP and other autoimmune diseases.
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