Background Severe IgE-mediated, food-induced anaphylactic reactions are characterized by pulmonary venous vasodilatation and fluid extravasation, which is thought to lead to the life-threatening anaphylactic phenotype. The underlying immunological and cellular processes involved in driving fluid extravasation and the severe anaphylactic phenotype are not fully elucidated. Objective To define the interaction and requirement of IL-4 and vascular endothelial (VE) IL-4Rα chain signaling in histamine-ABL1–mediated VE dysfunction and fluid extravasation in the severity of IgE-mediated anaphylactic reactions in mice. Methods Mice deficient in VE IL-4Rα and models of passive and active oral antigen– and IgE-induced anaphylaxis were employed to define the requirements of VE IL-4Rα and ABL1 pathway in severe anaphylactic reactions. Human VE cell line (EA.hy926 cells) and pharmacologic (imatinib) and genetic approaches (shRNA knockdown of IL4RA and ABL1) were used to define the requirement of this pathway in VE barrier dysfunction. Results IL-4 exacerbation of histamine-induced hypovolemic shock in mice was dependent on VE expression of the IL-4Rα. IL-4 and histamine induced ABL1 activation in human VE cells and VE barrier dysfunction was ABL1 dependent. Development of severe IgE-mediated hypovolemia and shock required VE-restricted ABL1 expression. Treatment of mice with a history of food-induced anaphylaxis with the ABL kinase inhibitor imatinib protected the mice from developing severe IgE-mediated anaphylaxis. Conclusion IL-4 amplifies IgE- and histamine-induced VE dysfunction, fluid extravasation, and severity of anaphylaxis via a VE IL-4Rα-ABL1–dependent mechanism. These studies implicate an important contribution by the VE compartment in the severity of anaphylaxis and identify a new pathway for therapeutic intervention of IgE-mediated reactions.

Background: Food-induced anaphylaxis (FIA) is an IgEdependent immune response that can affect multiple organs and lead to life-threatening complications. The processes by which food allergens cross the mucosal surface and are delivered to the subepithelial immune compartment to promote the clinical manifestations associated with food-triggered anaphylaxis are largely unexplored. Objective: We sought to define the processes involved in the translocation of food allergens across the mucosal epithelial surface to the subepithelial immune compartment in FIA. Methods: Two-photon confocal and immunofluorescence microscopy was used to visualize and trace food allergen passage in a murine model of FIA. A human colon cancer cell line, RNA silencing, and pharmacologic approaches were used From a the Mary H.

Cell cycle ↓ TP63 ↑ pCDK2 Esophageal epithelial proliferation Basal Zone Hyperplasia Identification of ANO1 as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis STAT6-Signal transducer and activator of transcription 6 ANO1-Anoctamin 1 TP63-Tumor protein P63 pCDK2-Phosphorylated cyclin dependent kinase 2 HCO 3-Bicarbonate Cl-Chlorine Background: The pathology of eosinophilic esophagitis (EoE) is characterized by eosinophil-rich inflammation, basal zone hyperplasia (BZH), and dilated intercellular spaces, and the underlying processes that drive the pathologic manifestations of the disease remain largely unexplored. Objective: We sought to investigate the involvement of the calcium-activated chloride channel anoctamin 1 (ANO1) in esophageal proliferation and the histopathologic features of EoE. Methods: We examined mRNA and protein expression of ANO1 in esophageal biopsy samples from patients with EoE and in From the Divisions of

Foundation; and the Sunshine Charitable Foundation and its supporters, Denise A. Bunning and David G. Bunning and the Mary H Weiser Food Allergy Center. Disclosure of potential conflict of interest: V. Mukkada is a consultant and receives research funding from Shire. M. E. Rothenberg is a consultant for PulmOne, Spoon Guru, ClostraBio, Celgene, Shire, AstraZeneca, GlaxoSmithKline, Allakos, Adare, Regeneron, and Novartis and has an equity interest in the first 4 listed and Immune Pharmaceuticals and receives royalties from reslizumab (Teva Pharmaceuticals) and UpToDate; he is also an inventor of patents owned by Cincinnati Children's Hospital Medical Center. S. P. Hogan is an inventor of patents owned by Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest.