Department of Developmental Genetics (H2), Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Respirology (B2), Graduate School of Medicine, Chiba University, Chiba, Japan.
Allergy. 2014 Feb;69(2):223-30. doi: 10.1111/all.12328. Epub 2013 Nov 29.
Polymorphisms of the Plant homeodomain finger protein 11 (PHF11) are strongly associated with high serum IgE levels and clinical severity of atopic patients. However, the precise mechanism has not been fully elucidated. We investigated the role of Phf11 in class switch recombination (CSR) to IgE by activated B cells.
We generated Phf11 transgenic (Lckd-Phf11-Tg) mice that express the exogenous murine Phf11 in lymphocytes under the control of distal Lck promoter. We examined IL-4-induced CSR to IgE in activated Lckd-Phf11-Tg B cells in vitro. We analyzed production of ovalbumin (OVA)-specific IgE and nose-scratching symptoms in Lckd-Phf11-Tg mice using an OVA-induced allergic rhinitis model.
The exogenous Phf11 promoted CSR to IgG1 and IgE in activated B cells with an increase in germ line transcript (GLT) γ1 and GLT ε expression. The exogenous Phf11 augmented transcriptional activity of the GLT γ1 and GLT ε promoters through permissive histone modifications and binding of NF-κB and STAT6. Furthermore, the exogenous Phf11 bound to the GLT ε promoter with increased binding of NF-κB. Silencing of the endogenous Phf11 reduced the frequency of CSR to IgE and GLT ε expression, but not to IgG1 or GLT γ1 expression, in activated B cells. In an allergic rhinitis model, Lckd-Phf11-Tg mice showed a significant increase in the production of OVA-specific IgE and the frequency of nose scratching.
Phf11 accelerates CSR to IgE in activated B cells by increasing the transcriptional activity of GLT ε promoter and contributes to the exacerbation of allergic responses. These findings provide a novel therapeutic target for allergic diseases.
植物同源结构域手指蛋白 11（PHF11）的多态性与高血清 IgE 水平和特应症患者的临床严重程度密切相关。然而，其确切机制尚未完全阐明。我们研究了 Phf11 在活化 B 细胞的类转换重组（CSR）向 IgE 中的作用。
我们生成了表达外源鼠 Phf11 的 Phf11 转基因（Lckd-Phf11-Tg）小鼠，该蛋白在淋巴细胞中受远端 Lck 启动子控制。我们在体外研究了 IL-4 诱导的活化 Lckd-Phf11-Tg B 细胞中的 CSR 向 IgE。我们使用卵清蛋白（OVA）诱导的变应性鼻炎模型分析了 Lckd-Phf11-Tg 小鼠中 OVA 特异性 IgE 的产生和鼻搔抓症状。
外源 Phf11 促进了活化 B 细胞中 IgG1 和 IgE 的 CSR，同时增加了 γ1 和 ε 基因的种系转录（GLT）。外源 Phf11 通过允许性组蛋白修饰和 NF-κB 和 STAT6 的结合，增强了 GLT γ1 和 GLT ε 启动子的转录活性。此外，外源 Phf11 与 GLT ε 启动子结合，NF-κB 的结合增加。在活化的 B 细胞中沉默内源性 Phf11 会降低 IgE 和 GLT ε 表达的 CSR 频率，但不影响 IgG1 或 GLT γ1 的表达。在变应性鼻炎模型中，Lckd-Phf11-Tg 小鼠表现出 OVA 特异性 IgE 产生和鼻搔抓频率的显著增加。
Phf11 通过增加 GLT ε 启动子的转录活性，加速活化 B 细胞中的 CSR 向 IgE，并有助于过敏反应的加剧。这些发现为过敏疾病提供了一个新的治疗靶点。
