Interleukin-17A Promotes IgE Production in Human B Cells
Interleukin-17A Promotes IgE Production in Human B Cells
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DOI：
10.1038/jid.2010.175
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发表时间：
2010-11-01
影响因子：
6.5
通讯作者：
Worm, Margitta
中科院分区：
文献类型：
--
作者：
Milovanovic, Milena;Drozdenko, Gennadiy;Worm, Margitta
最近，Th1/Th2的概念被修订，Th17细胞被认为与过敏有关。尽管有明确的相关证据，但IL-17A和IgE在变态反应中升高的细胞和分子基础尚未阐明。在这里，我们使用流式细胞术显示，与非过敏性供者相比，过敏性患者有更多的IL-17A+细胞。经IL-17A分泌检测后，从变态反应性供者外周血单核细胞中选择性去除IL-17A+细胞可降低IgE水平，而重新加入重组IL-17A可使其恢复，这表明重组IL-17A对IgE产生具有重要的功能意义。此外，酶联免疫斑点技术和酶联免疫吸附试验显示，IL-17A可直接促进抗CD40/IL-4共刺激下IgE分泌细胞的分化和IgE的产生。通过流式细胞术、免疫印迹和实时定量RT-PCR分析，IL-17A分别触发I-kappa Bα的快速降解和随后的NF-kappa B移位到B细胞核，随后是epsilon胚系的转录、激活诱导的胞苷脱氨酶和干扰素调节因子4的转录。我们的研究表明，IL-17A+细胞促进IgE的产生，IL-17A直接在B细胞水平发挥其促过敏作用。因此，IL-17A可能成为治疗包括特应性皮炎在内的IgE依赖型疾病的靶点。
Recently the Th1/Th2 concept has been revised and Th17 cells have been implicated in allergy. Despite clear correlative evidence, the cellular and molecular basis for the connection between increased IL-17A and IgE in allergy has not been elucidated. Here we show using flow cytometry that allergic patients have higher numbers of IL-17A+ cells compared to nonallergic donors. The selective removal of IL-17A+ cells from peripheral blood mononuclear cells of allergic donors after an IL-17A secretion assay reduces IgE levels, whereas re-addition of recombinant IL-17A restores it, as measured by ELISA, showing their important functional implication for IgE production. In addition, IL-17A directly promotes the differentiation of IgE-secreting cells and IgE production upon anti-CD40/IL-4 costimulation, as shown by enzyme-linked immunospot technique and ELISA. IL-17A triggers rapid degradation of I kappa B alpha and subsequent translocation of NF-kappa B into the B-cell nucleus, followed by transcription of epsilon germ-line, activation-induced cytidine deaminase, and IFN regulatory factor 4, as analyzed by flow cytometry, western blot, and quantitative real-time RT-PCR, respectively. Our study shows that IL-17A+ cells promote IgE production and that IL-17A exerts its pro-allergic effect directly at the level of B cells. Therefore, IL-17A might be a target for the treatment of IgE-dependent diseases, including atopic dermatitis.