The Cystic Fibrosis Transmembrane Regulator Controls Tolerogenic Responses to Food Allergens in Mice and Humans

IgE antibodies against the allergen Ara-h2 can cause life-threatening anaphylaxis upon exposure to peanuts. Desensitization strategies aim at inducing IgG responses against Ara-h2 which may compete with anaphylactogenic IgE. Here we assessed anti-Ara-h2 titers in an unselected cohort of 24,536 adult patients admitted to a general hospital for disparate medical reasons. Surprisingly, adult (n=177) and pediatric (n=76) patients with cystic fibrosis (pwCF) had IgG4, but not IgE, against several peanut and soybean allergens, yet did not suffer from peanut allergy. Antibody repertoires were not globally perturbed in pwCF, and heterozygous Cystic Fibrosis Transmembrane Regulator (CFTR) mutation carriers had the same prevalence of food allergies as pwCF. Peanut sensitisation of Cftr-/- mice failed to induce IgE and was associated with elevated IFN-{gamma}. We conclude that CFTR is a key regulator of anaphylactogenic and tolerogenic responses to food allergens. CFTR-controlled cytokine responses including IFN-{gamma}, in combination with a compromised epithelial barrier, may trigger a preferential IgG4 response resulting in tolerance to food allergens. HighlightsO_LIWe investigated serum IgG against Ara-h2 in 24,536 patients and identified 133 seropositives. C_LIO_LISeropositivity was associated with cystic fibrosis, and these patients had IgG4 but not IgE. C_LIO_LIWe reproduced these results in a paediatric validation cohort and in a Cftr-/- mouse model. C_LIO_LIA compromised epithelial barrier and the cytokine milieu might explain this phenotype. C_LI