Deletion of Wiskott-Aldrich Syndrome Protein in Regulatory T Cells Results in Spontaneous Allergic Sensitization to Food Antigens.

Patients and mice genetically deficient in Wiskott-Aldrich syndrome protein (WASp) have significantly elevated levels of serum IgE of poorly defined antigenic specificity. Here we show that WAS patients and WASp^-/- mice mount IgE and IgG responses against common human food allergens such as wheat and soy. Spontaneous food allergy in WASp^-/- animals developed independently of genetic background or colitis, and phenocopies human food allergy with small intestinal mast cell accumulation and improvement of allergic symptoms upon elimination diet. Sensitization was preserved in germfree WASp^-/- mice, was not transferrable to co-housed wild-type mice and could not be prevented by fostering of WASp^-/- pups by wild-type mothers. The antigen-specific IgE produced following oral ovalbumin administration in WASp^-/- mice mediated equally effective type I hypersensitivity reactions in vitro and in vivo when compared to an adjuvant-based model of food allergy in wild-type mice. Foxp3⁺ Tregs are critical to disease pathogenesis, as conditional deletion of WASp in Tregs resulted in exacerbated disease. We demonstrate that IgE/FcεRI-mediated signaling is impaired in WASp-deficient mast cells, accounting for the disparity in severity of intestinal Th2-type inflammation between complete and Treg-conditional WASp^-/- mice. Classification of food allergies in a cohort of 25 WAS patients revealed a prevalence of clinical food allergy of 20%, indicating that relative dampening of allergic responses by WASp^-/- mast cells is likely to be operative in human patients. In conclusion, our study demonstrates allergic sensitization to food as a feature of WASp-deficiency and establishes Treg-specific WASp^-/- mice as a spontaneous model of food allergy.