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
• 负责人: JOAN M COOK-MILLS
• 金额: $ 70.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10032718
• 关键词: 2 year old; 3-Dimensional; Affect; Age-Months; Allergens; Allergic; Allergy to peanuts; Alternaria; Anaphylaxis; Chickens; Child; Clinical; Clinical Research; Consumption; Data; Defect; Detection; Detergents; Development; Dose; Dust; Eczema; Exposure to; Food; Food Hypersensitivity; Foundations; Gene Mutation; Genes; Goals; Home environment; Human; IgE; Immune system; Immunotherapy; In Vitro; Induced Mutation; Infant; Intervention Studies; Learning; Life; Mediating; Modeling; Mus; Mutation; Neonatal; Oral; Ovalbumin; Pathway Analysis; Pathway interactions; Patients; Plasma; Predisposition; Pyroglyphidae; RNA; Reaction; Risk; Risk Factors; Sampling; Signal Transduction; Skin; Tail; Testing; Visual; blocking factor; early onset; egg; environmental allergen; food allergen; food antigen; food consumption; high risk; immune activation; innovation; keratinocyte; loss of function mutation; mouse model; neonate; novel; postnatal; pup; response; single-cell RNA sequencing; skin barrier; skin hypersensitivity; therapy design; transcriptome sequencing

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 食物过敏通常在生命的早期开始，可能会威胁生命。早期引入花生消费量是 建议减少花生过敏的发展。但是，在LEAP研究中，有14％的儿童不是 之所以包括，是因为它们在开始时对花生过敏呈阳性呈阳性，或者因为他们产生了反应 在口腔花生暴露期间。花生过敏与皮肤屏障基因的功能丧失突变有关。 在机械研究中，我们证明了具有杂合皮肤屏障突变的新生小鼠 食物过敏，通过皮肤共同暴露于洗涤剂，食物过敏原和无处不在的环境过敏原 Alternata（Alt）或房屋尘螨提取物。重要的是，在任何视觉上进行皮肤敏化 新生儿湿疹的证据。可以想象，对于儿童，食物抗原的皮肤敏化可能 发生在湿疹的临床体征之前。我们证明了皮肤敏化之前的口服花生消耗 抑制食物过敏的发展，但是这种抑制作用被口服花生期间的alt阻塞 消耗。这对于患有皮肤屏障缺陷的儿童可能很重要，但没有湿疹的早期迹象 在接受口服花生诱导耐受性的同时，暴露于无处不在的环境过敏原。在这个 提案，我们提出了一个新颖的概念，即有皮肤衍生的系统因素可以阻止耐受性和 这可以作为食物过敏发展的风险因素，而且有些皮肤衍生的因素可能 在口服食用食物过敏原之前，可以预测对食物过敏的敏化。我们的初步数据 来自新生小鼠的敏化皮肤的散装和单细胞RNA-seq分析表明信号定义 环境过敏原的独特功能，用于诱导食物过敏和信号，这是独特的 ALT和食物过敏原的新生儿与皮肤屏障突变的结合。我们的长期目标是 确定通过皮肤暴露对食物过敏的机制，并确定因素发现风险的因素 皮肤敏化。作为朝着我们长期目标的一步，我们的中心假设是食物过敏的启动 通过皮肤暴露于过敏原是由皮肤的信号介导的，其屏障突变会诱导细胞网络 激活免疫系统以生成过敏原特异性IgE的信号。我们将检验我们的中心假设 以以下目的：目标1。测试皮肤和屏障突变的假设，受到食物过敏原的刺激 环境过敏原产生的因素a）是全身信号，b）可以阻止口服食物抗原引起的 耐受性和c）可以调解对食物过敏发展的敏感性。目标2。检验假设 食物过敏的开始是由皮肤带有屏障突变表达的识别分子介导的。目标3。 测试过敏原通过皮肤屏障基因缺陷（FLG或TMEM79）刺激角质形成细胞的假设 在RNA-seq分析中诱导一组常见因素表达的途径。