Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy
Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy
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DOI：
10.1016/j.jaci.2017.02.035
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发表时间：
2018-01-01
影响因子：
14.2
通讯作者：
Noti, Mario
中科院分区：
文献类型：
--
作者：
Hussain, Maryam;Borcard, Loic;Noti, Mario
背景：胸腺基质淋巴细胞生成素（TSLP）的过量产生和嗜碱性粒细胞的浸润与特应性皮炎（AD）的发病机制有关，特应性皮炎是食物过敏发生的公认危险因素。尽管 TSLP 和嗜碱性粒细胞与表皮致敏反应中食物诱发的过敏性疾病有关，但 TSLP 引发的嗜碱性粒细胞引导皮肤过敏性炎症进展至远处粘膜部位（例如胃肠道）的机制尚不清楚。 目的：我们试图测试嗜碱性粒细胞固有的 IL-4 产生在皮肤对食物抗原的 TH2 致敏和效应食物诱导中的作用。方法：在 AD 样皮肤病变上用卵清蛋白对小鼠进行表皮致敏，然后进行胃内抗原激发以诱导 IgE 介导的食物过敏。通过使用幼稚 T 细胞共培养实验，在体外评估了 TH2 极化对嗜碱性粒细胞衍生的 IL-4 产生的需求，以及 IgE 介导的食物过敏的发病机制，并通过使用选择性缺乏嗜碱性粒细胞中 IL-4 产生的 Il4 3'UTR 小鼠进行体内评估。结果：表皮食物抗原致敏与具有 IL-4 能力的先天免疫细胞浸润到皮肤有关，其中嗜碱性粒细胞和嗜酸性粒细胞代表优势人群。与嗜碱性粒细胞相反，嗜酸性粒细胞的缺失不会改变疾病结果。将具有 IL-4 能力的嗜碱性粒细胞与树突状细胞和初始 T 细胞共培养，足以在体外以 IL-4 依赖性方式促进 TH2 极化，而体内嗜碱性粒细胞固有的 IL-4 生成缺失与食物诱导的过敏反应减少有关。 结论：TSLP 诱导的嗜碱性粒细胞通过 IL-4 促进表皮对食物抗原的敏感性以及随后 IgE 介导的食物过敏。针对 AD 患者的 TSLP-嗜碱性粒细胞-IL-4 轴的策略可能会带来创新疗法，从而预防远处粘膜部位的过敏进展。
Background: Exaggerated thymic stromal lymphopoietin (TSLP) production and infiltration of basophils are associated with the pathogenesis of atopic dermatitis (AD), a recognized risk factor for the development of food allergies. Although TSLP and basophils have been implicated in promotion of food-induced allergic disorders in response to epicutaneous sensitization, the mechanisms by which TSLP-elicited basophils guide the progression of allergic inflammation in the skin to distant mucosal sites, such as the gastrointestinal tract, are poorly understood.Objective: We sought to test the role of basophil-intrinsic IL-4 production in TH2 sensitization to food antigens in the skin and effector food-induced allergic responses in the gut.Methods: Mice were epicutaneously sensitized with ovalbumin on an AD-like skin lesion, followed by intragastric antigen challenge to induce IgE-mediated food allergy. The requirement for basophil-derived IL-4 production for TH2 polarization and the pathogenesis of IgE-mediated food allergy was assessed in vitro by using coculture experiments with naive T cells and in vivo by using Il4 3'UTR mice that selectively lack IL-4 production in basophils.Results: Epicutaneous food antigen sensitization is associated with infiltration of IL-4-competent innate immune cells to the skin, with basophils and eosinophils representing the predominant populations. In contrast to basophils, absence of eosinophils did not alter disease outcome. Coculture of IL-4-competent basophils together with dendritic cells and naive T cells was sufficient to promote TH2 polarization in an IL-4-dependent manner in vitro, whereas absence of basophil-intrinsic IL-4 production in vivo was associated with reduced food-induced allergic responses.Conclusion: TSLP-elicited basophils promote epicutaneous sensitization to food antigens and subsequent IgE-mediated food allergy through IL-4. Strategies to target the TSLP-basophil-IL-4 axis in patients with AD might lead to innovative therapies that can prevent the progression of allergies to distant mucosal sites.