Mechanisms for initiation of food allergy early in life

项目摘要 食物过敏通常在生命早期就开始了，可能危及生命。花生消费的早期介绍是 建议减少花生过敏的发展。然而，在LEAP研究中，14%的儿童没有 包括因为他们在一开始对花生过敏的皮肤刺激性阳性，或者因为他们产生了反应 在口服花生的过程中。花生过敏与皮肤屏障基因功能丧失突变有关。 在机制研究中，我们证明了具有杂合皮肤屏障突变的新生小鼠发生了 皮肤同时接触洗涤剂、食物过敏原和一种普遍存在的环境过敏原--链格孢霉引起的食物过敏 Alt(Alt)或屋尘螨精华。重要的是，皮肤敏化是在任何视觉检查之前进行的 新生儿有湿疹的迹象。可以想象，对于儿童来说，用食物抗原进行皮肤致敏可以 发生在湿疹的临床症状之前。我们证明，在皮肤致敏之前，口服花生 抑制食物过敏的发展，但这种抑制作用可被口服花生时皮肤上的Alt所阻断 消费。这对于有皮肤屏障缺陷但没有湿疹早期迹象的儿童来说可能很重要，谁 在口服花生诱导耐受的过程中暴露于无处不在的环境过敏原。在这 提议，我们发展了一个新的概念，即存在皮肤衍生的系统性因素，阻止耐受性和 可以作为食物过敏发展的风险因素，而且，有皮肤衍生的因素可能 在口服食物过敏原前预测食物过敏的存在。我们的初步数据 对新生小鼠致敏皮肤的散装和单细胞rna-seq分析表明， 环境过敏原诱导食物过敏的独特功能和独特的信号 皮肤屏障突变新生儿的Alt和食物过敏原暴露的联合。我们的长期目标是 确定皮肤暴露引起食物过敏的机制，并确定检测风险的因素 皮肤敏感化。作为迈向我们长期目标的一步，我们的中心假设是食物过敏的启动 皮肤接触变应原是由皮肤发出的信号介导的，这种信号带有诱导细胞网络的屏障突变 激活免疫系统以产生过敏原特异性IgE的信号。我们将检验我们的中心假设 其目的如下：目标1.检验具有屏障突变的皮肤受食物过敏原刺激的假设 而环境过敏原产生的因素A)是全身信号，B)可以阻断口服食物抗原诱导的 耐受性和C)可以调节对食物过敏的易感性。目标2.检验假设 食物过敏的启动是由带有屏障突变的皮肤表达的识别分子介导的。目标3. 验证变应原通过以下途径刺激皮肤屏障基因缺陷的角质形成细胞(Flg或Tmen79)的假设 聚合以诱导在RNA-SEQ分析中检测到的一组公共因子的表达的途径。

PROJECT ABSTRACT Food allergy often starts early in life and can be life threatening. Early introduction of peanut consumption is recommended to reduce development of peanut allergy. However, in the LEAP study, 14% of children were not included because they were skin prick positive for peanut allergy at the start or because they developed reactions during oral peanut exposures. Peanut allergy is associated with loss-of-function mutations in skin barrier genes. In mechanistic studies, we demonstrated that neonatal mice with heterozygous skin barrier mutations developed food allergy by skin co-exposure to detergent, food allergen and a ubiquitous environmental allergen, Alternaria alternata (Alt) or house dust mite extract. Importantly, the skin sensitizations were performed before any visual evidence of eczema in the neonates. It is conceivable that for children, skin sensitization with food antigens could occur before clinical signs of eczema. We demonstrated that oral peanut consumption before skin sensitization inhibited development of food allergy, but this inhibition was blocked by Alt on the skin during oral peanut consumption. This may be important for children with skin barrier defects but without early signs of eczema, who are exposed to ubiquitous environmental allergens while undergoing oral peanut induction of tolerance. In this proposal, we develop the novel concept that there are skin-derived systemic factors that block tolerance and that can serve as risk factors for development of food allergy, and that, there are skin-derived factors that may predict existence of sensitization to food allergy before oral consumption of food allergens. Our preliminary data from bulk and single cell RNA-seq analyses of sensitized skin from neonatal mice indicate signals that define unique function of environmental allergen for induction of food allergy and signals that are unique to the combination of Alt and food allergen exposure of neonates with skin barrier mutations. Our long-term goal is to identify mechanisms for initiation of food allergy by skin exposures and identify factors for detection of risk for skin sensitization. As a step towards our long-term goal, our central HYPOTHESIS is that initiation of food allergy by skin exposure to allergen is mediated by signals from skin with barrier mutations that induce a network of cell signals for activation of the immune system to generate allergen-specific IgE. We will test our central hypothesis with the following aims: Aim 1. Test the hypotheses that skin, with barrier mutations, stimulated by food allergens and environmental allergens produce factors that A) are systemic signals, B) can block oral food antigen-induced tolerance and C) can mediate susceptibility to development of food allergy. Aim 2. Test the hypothesis that initiation of food allergy is mediated by recognition molecules expressed by skin with barrier mutations. Aim 3. Test the hypothesis that allergen stimulates keratinocytes with defects in skin barrier genes (Flg or Tmem79) via pathways that converge to induce expression of a common set of factors detected in the RNA-seq analysis.