Mechanisms for initiation of food allergy early in life

生命早期发生食物过敏的机制

基本信息

项目摘要

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.
项目摘要 食物过敏通常发生在生命早期,并可能危及生命。早期引进花生消费是 建议减少花生过敏的发生。然而,在 LEAP 研究中,14% 的儿童没有 包括在内,因为他们一开始对花生过敏的皮肤点刺呈阳性,或者因为他们出现了反应 在口服花生暴露期间。花生过敏与皮肤屏障基因的功能丧失突变有关。 在机制研究中,我们证明具有杂合皮肤屏障突变的新生小鼠发育 皮肤同时接触洗涤剂、食物过敏原和普遍存在的环境过敏原链格孢属而引起的食物过敏 链格孢 (Alt) 或屋尘螨提取物。重要的是,皮肤过敏是在任何视觉之前进行的 新生儿湿疹的证据。可以想象,对于儿童来说,食物抗原引起的皮肤过敏可能会 发生在湿疹临床症状之前。我们证明,在皮肤过敏之前口服花生 抑制食物过敏的发展,但口服花生期间这种抑制作用被皮肤上的 Alt 阻断 消耗。这对于有皮肤屏障缺陷但没有湿疹早期迹象的儿童可能很重要,他们 在接受口服花生诱导耐受时暴露于无处不在的环境过敏原。在这个 提案中,我们提出了一个新概念,即存在皮肤源性系统因素,可以阻止耐受性和 这可以作为食物过敏的危险因素,并且皮肤源性因素可能会导致食物过敏。 在口服食物过敏原之前预测是否存在食物过敏。我们的初步数据 对新生小鼠致敏皮肤的批量和单细胞 RNA-seq 分析显示了定义的信号 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 和食物过敏原暴露相结合。我们的长期目标是 确定皮肤接触引发食物过敏的机制,并确定检测食物过敏风险的因素 皮肤过敏。作为实现我们长期目标的一步,我们的中心假设是食物过敏的发生 皮肤接触过敏原是由来自皮肤的信号介导的,该信号具有诱导细胞网络的屏障突变 激活免疫系统产生过敏原特异性 IgE 的信号。我们将检验我们的中心假设 目标如下: 目标 1. 测试具有屏障突变的皮肤受到食物过敏原刺激的假设 环境过敏原产生的因子 A) 是全身信号,B) 可以阻断口腔食物抗原诱导的 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 食物过敏的引发是由具有屏障突变的皮肤表达的识别分子介导的。目标3。 测试过敏原刺激皮肤屏障基因(Flg 或 Tmem79)缺陷的角质形成细胞的假设: 汇聚诱导 RNA-seq 分析中检测到的一组常见因子表达的途径。

项目成果

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JOAN M COOK-MILLS其他文献

JOAN M COOK-MILLS的其他文献

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{{ truncateString('JOAN M COOK-MILLS', 18)}}的其他基金

Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
  • 批准号:
    10653024
  • 财政年份:
    2020
  • 资助金额:
    $ 65.36万
  • 项目类别:
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
  • 批准号:
    10032718
  • 财政年份:
    2020
  • 资助金额:
    $ 65.36万
  • 项目类别:
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
  • 批准号:
    10203801
  • 财政年份:
    2020
  • 资助金额:
    $ 65.36万
  • 项目类别:
Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants
新生儿和婴儿对过敏原反应性发展的脂质调节
  • 批准号:
    9323656
  • 财政年份:
    2017
  • 资助金额:
    $ 65.36万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    9981971
  • 财政年份:
    2017
  • 资助金额:
    $ 65.36万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    9380183
  • 财政年份:
    2017
  • 资助金额:
    $ 65.36万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    10160774
  • 财政年份:
    2017
  • 资助金额:
    $ 65.36万
  • 项目类别:
Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants
新生儿和婴儿对过敏原反应性发展的脂质调节
  • 批准号:
    9919537
  • 财政年份:
    2017
  • 资助金额:
    $ 65.36万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    9925738
  • 财政年份:
    2017
  • 资助金额:
    $ 65.36万
  • 项目类别:
5 -Hydroxytryptophan Regulation of Endothelial Cell Signals for Lung Inflammation
5-羟基色氨酸对肺部炎症内皮细胞信号的调节
  • 批准号:
    8711545
  • 财政年份:
    2013
  • 资助金额:
    $ 65.36万
  • 项目类别:

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