Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin–basophil axis

Abstract

Background Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy. Objective To test the immunological mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy. Methods Mice were epicutaneously sensitized with ovalbumin (OVA) or peanut on an atopic dermatitis-like skin lesion followed by intragastric antigen challenge. Antigen-specific serum IgE levels and Th2 cytokine responses were measured by ELISA. Expression of type-2 cytokines and mast cell proteases in the intestine were measured by real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by flow cytometry. In vivo basophil depletion was achieved by diphtheria toxin treatment of Baso-DTR mice. For cell transfer studies, the basophil population was expanded in vivo by hydrodynamic tail vein injection of thymic stromal lymphopoietin cDNA plasmid. Results Sensitization to food allergens through an atopic dermatitis-like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific Th2 cytokine responses, elevated antigen-specific serum IgE levels and the accumulation of mast cells in the intestine promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy while transfer of TSLP-elicited basophils into intact skin promoted disease. Conclusion Epicutaneous sensitization on a disrupted skin barrier is associated with the accumulation of TSLP-elicited basophils that are necessary and sufficient to promote antigen-induced intestinal food allergy.

IgA deficiency: a risk factor for food allergy-related atopic dermatitis in infants and young children

“…This finding is consistent with observations also made by other authors who reported an association of impaired antibody production with atopic dermatitis in children [6,18], and which was also found in our previous study [19]. Interestingly, it has been shown recently that cutaneous sensitization may predispose patients to an intestinal allergy by the increased production of thymic stromal lymphopoietin (TSLP) and subsequent T-helper type 2 (Th2)-dependent immune responses to food antigens in the skin [20,21]. These studies may be helpful in understanding the mechanisms by which atopic dermatitis progresses to allergic immune responses at other mucosal surfaces [11] and shedding light on the role of atopic dermatitis in development of food allergy in hypogammaglobulinemic children predisposed to damage at the large surface area of the skin and mucous membrane of the gastrointestinal tract.…”

Histamine-releasing factor enhances food allergy

“…A crucial role for FcεRI in food allergy was previously demonstrated in this and other murine models (9,21). We confirmed it using FceRIa -/-mice, as allergic diarrhea was severely delayed and suppressed in FceRIa -/-mice.…”

“…(I) Distribution of HRF-reactive IgE and egg white-specific IgE levels before OIT in egg-allergy patients (n = 37). followed by oral challenge with OVA, basophil-depleted or TSLP receptor-deficient mice were shown to not produce OVA-specific IgE and to be protected from oral challenge-induced anaphylaxis (21,41). Epicutaneous sensitization of mice with OVA and TSLP, followed by oral challenges with OVA, resulted in IL-25-dependent diarrhea and anaphylaxis (42).…”

“…Thus, basophils and TSLP have pivotal roles in Th2 development in the skin during the sensitization phase of food allergy. In contrast, while IL-33 is dispensable for promoting cutaneous antigen sensitization, it is essential for inducing IgEdependent anaphylaxis in the gut (21,41). Transgenic overexpression of IL-25 promoted the susceptibility to food allergy, whereas IL-25 receptor-deficient (IL-17RB-deficient) mice were resistant to food allergy induction.…”

Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity

“…In adult patients with EoE, airway allergy precedes EoE (50). Recent data suggest that an epicutaneous sensitization with ovalbumin may result in an antigen-induced gastrointestinal food allergy via the TSLP-basophil axis or in an IL-17-mediated response depending on the animal model (51,52). Furthermore, filaggrin mutations as risk factors for eczema, the atopic march and peanut allergy have been reported, indicating that an impaired epithelial barrier function may predispose to allergen sensitization and atopy (53,54).…”