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

作者：Marc Emmenegger, Chrysoula Zografou, Yile Dai, Laura R. Hoyt, Ravindra Gudneppanavar, Andra Chincisan, Hubert Rehrauer, Falko Noé, Natalia Zajac, Georg Meisl, Matthias M. Schneider, Hang Thi Thu Nguyen, Katja Höpker, Tuomas P. J. Knowles, Mireia Sospedra, Roland Martinꝉ, Aaron M. Ring, Stephanie Leeds, Stephanie C. Eisenbarth, Marie E. Egan, Emanuela M. Bruscia, Adriano Aguzzi · 发表于：medRxiv · 年份：2024 · DOI：10.1101/2024.06.17.24309019 · 被引用次数：5 · 研究领域：Consumer Attitudes and Food Labeling、Food Allergy and Anaphylaxis Research、Cystic Fibrosis Research Advances

Abstract 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-γ. We conclude that CFTR is a key regulator of anaphylactogenic and tolerogenic responses to food allergens. CFTR-controlled cytokine responses including IFN-γ, in combination with a compromised epithelial barrier, may trigger a preferential IgG4 response resulting in tolerance to food allergens. Highlights We investigated serum IgG against Ara-h2 in 24,536 patients and identified 133 seropositives. Seropositivity was associated with cystic fibrosis, and these patients had IgG4 but not IgE. We reproduced these results in a paediatric validation cohort and in a Cftr -/- mouse model. A compromised epithelial barrier and the cytok...