Molecular Genomics and Genetics Group, National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
Sci Rep. 2016 Nov 29;6:37988. doi: 10.1038/srep37988.
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed. CCL22 and CCL17 were dramatically induced but followed a temporal trajectory distinct from classical mediators of isotype switching. AICDA, NFIL3, IRF4, XBP1 and BATF3 shared a profile with several genes involved in innate immunity, but with no recognised role in CSR. A transcription factor BHLHE40 was identified at the core of this profile. B-cell activation was also accompanied by variation in exon retention affecting >200 genes including CCL17. The data indicate a circadian component and central roles for the Th2 chemokines CCL22 and CCL17 in the activation of CSR.
免疫球蛋白类别转换重组（CSR）到 IgE 是一种紧密调控的过程，是特应性疾病的核心。为了描绘导致 IgE 产生的生发中心活动激活所涉及的 B 细胞转录反应，用 IL-4 和抗 CD40 刺激幼稚的人 B 细胞。使用 Affymetrix Human Exon 1.0 ST Array 在 12 天内对基因表达和选择性剪接进行了分析。总共 1399 个基因，形成 13 个时间表达谱，差异表达。CCL22 和 CCL17 被显著诱导，但与经典的同种型转换介质的时间轨迹不同。AICDA、NFIL3、IRF4、XBP1 和 BATF3 与几个参与先天免疫的基因具有相似的表达谱，但在 CSR 中没有公认的作用。转录因子 BHLHE40 被确定为该表达谱的核心。B 细胞激活还伴随着影响包括 CCL17 在内的 200 多个基因的外显子保留的变化。这些数据表明，Th2 趋化因子 CCL22 和 CCL17 在 CSR 的激活中存在昼夜节律成分和核心作用。
