Background

Mechanisms for the development of food allergy in neonates are unknown but clearly linked in patient populations to a genetic predisposition to skin barrier defects. Whether skin barrier defects contribute functionally to development of food allergy is unknown.

Objective

The purpose of the study was to determine whether skin barrier mutations, which are primarily heterozygous in patient populations, contribute to the development of food allergy.

Methods

Mice heterozygous for the filaggrin (Flg)^ft and Tmem79^ma mutations were skin sensitized with environmental and food allergens. After sensitization, mice received oral challenge with food allergen, and then inflammation, inflammatory mediators, and anaphylaxis were measured.

Results

We define development of inflammation, inflammatory mediators, and food allergen–induced anaphylaxis in neonatal mice with skin barrier mutations after brief concurrent cutaneous exposure to food and environmental allergens. Moreover, neonates of allergic mothers have increased responses to suboptimal sensitization with food allergens. Importantly, responses to food allergens by these neonatal mice were dependent on genetic defects in skin barrier function and on exposure to environmental allergens. ST2 blockade during skin sensitization inhibited the development of anaphylaxis, antigen-specific IgE, and inflammatory mediators. Neonatal anaphylactic responses and antigen-specific IgE were also inhibited by oral pre-exposure to food allergen, but interestingly, this was blunted by concurrent pre-exposure of the skin to environmental allergen.

Conclusion

These studies uncover mechanisms for food allergy sensitization and anaphylaxis in neonatal mice that are consistent with features of human early-life exposures and genetics in patients with clinical food allergy and demonstrate that changes in barrier function drive development of anaphylaxis to food allergen.

中文翻译：

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引发食物过敏的机制：取决于皮肤屏障突变和环境过敏原共刺激

背景

新生儿食物过敏的发展机制尚不清楚，但在患者人群中与皮肤屏障缺陷的遗传易感性明显相关。皮肤屏障缺陷是否在功能上有助于食物过敏的发展尚不清楚。

客观的

该研究的目的是确定在患者人群中主要是杂合的皮肤屏障突变是否有助于食物过敏的发展。

方法

皮肤致敏蛋白（Flg）^ft和Tmem79 ^ma突变的杂合小鼠被环境和食物过敏原致敏。致敏后，小鼠接受食物过敏原进行口服攻击，然后测量炎症，炎症介质和过敏反应。

结果

在短暂并发皮肤接触食物和环境变应原后，我们定义了具有皮肤屏障突变的新生小鼠的炎症，炎症介质和食物变应原诱发的过敏反应的发展。此外，过敏性母亲的新生儿对食物过敏原的次佳致敏反应增强。重要的是，这些新生小鼠对食物过敏原的反应取决于皮肤屏障功能的遗传缺陷和环境过敏原的暴露。皮肤致敏过程中的ST2阻滞抑制了过敏反应，抗原特异性IgE和炎症介质的发展。口服食物暴露原也可抑制新生儿的过敏反应和抗原特异性IgE，但有趣的是，皮肤同时暴露于环境变应原也可抑制这种反应。

结论

这些研究揭示了对新生小鼠食物过敏的致敏和过敏反应机制，这些机制与临床食物过敏患者的人类早期生命暴露和遗传学特征一致，并证明了屏障功能的变化驱动了对食物过敏原的过敏反应发展。