STAT3 Signaling in B Cells Is Critical for Germinal Center Maintenance and Contributes to the Pathogenesis of Murine Models of Lupus.
STAT3 Signaling in B Cells Is Critical for Germinal Center Maintenance and Contributes to the Pathogenesis of Murine Models of Lupus.
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DOI：
10.4049/jimmunol.1502043
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发表时间：
2016-06-01
期刊：
影响因子：
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通讯作者：
Yan J
中科院分区：
文献类型：
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作者：
Ding C;Chen X;Dascani P;Hu X;Bolli R;Zhang HG;Mcleish KR;Yan J
抗体成熟、记忆B和浆细胞分化主要发生在生发中心(GC)。系统性红斑狼疮(SLE)可能是GC活性增强的结果。以往的研究表明，信号转导和转录激活子3(STAT3)通路异常与狼疮的发病有关。然而，STAT3在调节SLE疾病进展中的确切作用尚不完全清楚。在这里，我们证明了B细胞中的STAT3信号对GC的形成和维持以及抗体反应是必不可少的。在STAT3基因缺失的GC B细胞中，细胞凋亡率增加，抗凋亡基因Bclxl和Mcl 1表达下调。免疫B细胞STAT3缺陷小鼠的Tfh细胞应答与GC B细胞呈正相关，且显著降低。STAT3缺乏也导致浆细胞分化障碍。此外，自身反应性B细胞中的STAT3缺乏会导致自身抗体的产生减少。在B细胞STAT3缺陷的B6.MRL/LPR小鼠中的结果表明，STAT3信号通过调节GC反应性、自身抗体的产生和肾脏病理而在SLE的发病机制中发挥重要作用。我们的发现为STAT3信号在维持GC形成和GC B细胞分化中的作用提供了新的见解，并确认STAT3是治疗SLE的新靶点。
Antibody maturation as well as memory B and plasma cell differentiation occur primarily in the germinal centers (GC). Systemic lupus erythemotosus (SLE) may develop as a result of enhanced GC activity. Previous studies have shown that the dysregulated signal transducer and activator of transcription 3 (STAT3) pathway is linked to lupus pathogenesis. However, the exact role of STAT3 in regulating SLE disease progression has not been fully understood. Here, we demonstrated that the STAT3 signaling in B cells is essential for the GC formation and maintenance as well as antibody response. Increased cell apoptosis and down-regulated Bcl-xL and Mcl-1 anti-apoptotic gene expression were found in the STAT3 deficient GC B cells. The Tfh cell response positively correlated with the GC B cells and was significantly decreased in immunized B cell STAT3-deficient mice. STAT3 deficiency also led to the defect of plasma cell differentiation. Furthermore, STAT3 deficiency in autoreactive B cells resulted in decreased autoantibody production. Results obtained from B-cell STAT3 deficient B6.MRL/lpr mice suggest that STAT3 signaling significantly contributes to the SLE pathogenesis by regulation of the GC reactivity, autoantibody production, and kidney pathology. Our findings provide new insights into the role of STAT3 signaling in the maintenance of the GC formation and GC B cell differentiation and identify STAT3 as a novel target for the treatment of SLE.