Communication between skin and gastrointestinal tract in food allergy

 描述(由申请人提供)：免疫球蛋白介导的食物过敏影响大约5%-8%的美国人口，目前还没有批准的治疗方法。目前的管理策略包括避免过敏原，但意外摄入是患者的常见经历。反应的严重程度是不可预测的，范围从轻微的麻疹到危及生命的全身过敏反应。过敏通常发生在生命的第一年，食物过敏的最具预测性的风险因素是湿疹。一种正在发展的范例是，通过家庭粉尘接触食物会促进湿疹儿童对食物的皮肤过敏，而避免饮食则会阻止正常的口腔耐受性发展。根据初步数据，我们假设来自皮肤的炎症信号也可能有助于对口服途径遇到的食物的敏化。使用模拟特应性皮炎剥离的胶带剥离模型，我们观察到一次轻微的皮肤损伤会导致小肠固有免疫环境的显著变化。胃肠道固有细胞和前体细胞诱导Th2细胞因子的表达，以及固有细胞流入粘膜免疫系统的诱导部位。此外，在没有皮肤表面过敏原暴露的情况下，胶带剥离支持在反复给小鼠喂食该抗原时产生过敏症状。根据我们的初步数据，我们假设，受损的皮肤屏障产生的信号系统地作用于从骨髓释放胃肠道组织的祖细胞，此外还驱动胃肠道组织驻留细胞的先天Th2反应。这种偏向的先天免疫环境因此促进了粘膜组织中IgE类的转换，损害了口腔耐受性的发展。我们将在两个具体目标上检验这一假设。在第一个目标中，我们将确定皮肤损伤导致胃肠道组织免疫环境改变的机制。我们将检测轻度磁带剥离损伤对骨髓、血液、皮肤和胃肠道组织中先天和祖细胞的影响，并使用报告研究其细胞因子的表达。 老鼠。我们将确定皮肤细胞因子在驱动胃肠道这种先天免疫反应中的作用。在下一个目标中，我们将利用食物过敏的小鼠模型来确定这种改变的免疫环境对食物抗原的耐受性或敏感度的发展的功能后果。此外，我们将研究改变的免疫环境对Tfh细胞和Treg细胞生成的影响，以及类向IgE的转换。成功完成我们的目标将使我们对皮肤在食物过敏发展中的作用有一个机械性的理解，并将帮助我们设计适当的策略来预防生命早期的食物过敏。

 DESCRIPTION (provided by applicant): IgE-mediated food allergy affects approximately 5-8% of the US population, and there is no approved treatment. The current management strategy consists of allergen avoidance, but accidental ingestions are a common experience for patients. Severity of reactions is not predictable, and can range from mild hives to life- threatening systemic anaphylaxis. Sensitization commonly occurs in the first year of life, and the most predictive risk factor for food allergy is eczema. A developing paradigm is that exposure to foods via household dust promotes epicutaneous sensitization to foods in children with eczema, while dietary avoidance prevents the normal development of oral tolerance. Based on preliminary data, we hypothesize that inflammatory signals from the skin may also contribute to sensitization to foods encountered by the oral route. Using a model of tape-stripping that mimics the excoriations of atopic dermatitis, we observed that a single episode of mild skin damage leads to a significant change in the innate immune milieu of the small intestine. There is an induction of Th2 cytokine expression by resident innate and progenitor cells of the gastrointestinal tract, as well as an influx of innate cells into the inductive sites of the mucosa immune system. Furthermore, tape stripping in the absence of epicutaneous allergen exposure supports the generation of allergic symptoms when mice are repeatedly fed with the antigen. Based on our preliminary data, we hypothesize that signals generated from a compromised skin barrier act systemically to release progenitors from the bone marrow that home to the gastrointestinal tissues, and in addition drive an innate Th2 response from resident cells of the gastrointestinal tissues. This biased innate immune milieu thereby promotes IgE class switch in the mucosal tissues and impairs the development of oral tolerance. We will test this hypothesis in two specific aims. In the first aim, we will determine the mechanism by which damage to the skin leads to an altered immune milieu in the gastrointestinal tissues. We will examine the impact of mild tape stripping-induced injury on innate and progenitor cells in bone marrow, blood, skin, and gastrointestinal tract tissues, and study their cytokine expression using reporter mice. We will determine the role of skin cytokines in driving this innate immune response in the gastrointestinal tract. In the next aim we will determine the functional consequence of this altered immune milieu on the development of tolerance or sensitization to food antigens using mouse models of food allergy. Furthermore, we will examine the impact of the altered immune milieu on generation of Tfh cells and Tregs as well as class switch to IgE. Successful completion of our aims will provide us with a mechanistic understanding of the role of the skin in development of food allergy, and will help us to design appropriate strategies for the prevention of food allergy in early life.