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Current knowledge cannot explain why only some individuals among those with food allergy are prone to develop life-threatening anaphylaxis. It is increasingly evident that the immunologic mechanisms involved in developing IgE-mediated food allergy are far more complex than allergic sensitization. Clinical observations suggest that patients who develop severe allergic reactions to food are often sensitized through the skin in early infancy. Environmental insults trigger epidermal thymic stromal lymphopoietin and interleukin-33 (IL-33) production, which endows dendritic cells with the ability to induce CD4<ns4:sup>+<\/ns4:sup>TH2 cell-mediated allergic inflammation. Intestinal IL-25 propagates the allergic immune response by enhancing collaborative interactions between resident type-2 innate lymphoid cells and CD4<ns4:sup>+<\/ns4:sup>TH2 cells expanded by ingested antigens in the gastrointestinal tract. IL-4 signaling provided by CD4<ns4:sup>+<\/ns4:sup>TH2 cells induces emigrated mast cell progenitors to become multi-functional IL-9-producing mucosal mast cells, which then expand greatly after repeated food ingestions. Inflammatory cytokine IL-33 promotes the function and maturation of IL-9-producing mucosal mast cells, which amplify intestinal mastocytosis, resulting in increased clinical reactivity to ingested food allergens. These findings provide the plausible view that the combinatorial signals from atopic status, dietary allergen ingestions, and inflammatory cues may govern the perpetuation of allergic reactions from the skin to the gut and promote susceptibility to life-threatening anaphylaxis. Future in-depth studies of the molecular and cellular factors composing these stepwise pathways may facilitate the discovery of biomarkers and therapeutic targets for diagnosing, preventing, and treating food allergy.<\/ns4:p>","DOI":"10.12688\/f1000research.9497.1","type":"journal-article","created":{"date-parts":[[2016,11,10]],"date-time":"2016-11-10T09:55:06Z","timestamp":1478771706000},"page":"2660","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Developing food allergy: a potential immunologic pathway linking skin barrier to 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US Department of Defense (W81XWH-15-1-0517), the Digestive Health Center (P30DK078392), and the American Partnership for Eosinophilic Disorders. 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