title: Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33-basophil axis in mice.
abstract: Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder characterized by accumulation of eosinophils in the esophagus. EoE often coexists with atopic dermatitis, a chronic inflammatory skin disease. The impaired skin barrier in patients with atopic dermatitis has been suggested as an entry point for allergic sensitization that triggers development of EoE.
  
  
  
  We sought to define the mechanisms whereby epicutaneous sensitization through a disrupted skin barrier induces development of EoE.
  
  
  
  To elicit experimental EoE, mice were epicutaneously sensitized with ovalbumin (OVA), followed by intranasal OVA challenge. Levels of esophageal mRNA for TH2 cytokines and the IL-33 receptor Il1rl1 (St2) were measured by using quantitative PCR. Esophageal eosinophil accumulation was assessed by using flow cytometry and hematoxylin and eosin staining. In vivo basophil depletion was achieved with diphtheria toxin treatment of Mcpt8DTRmice, and animals were repopulated with bone marrow basophils. mRNA analysis of esophageal biopsy specimens from patients with EoE was used to validate our findings in human subjects.
  
  
  
  Epicutaneous sensitization and intranasal challenge of wild-type mice resulted in accumulation of eosinophils and upregulation of TH2 cytokines and St2 in the esophagus. Disruption of the IL-33-ST2 axis or depletion of basophils reduced these features. Expression of ST2 on basophils was required to accumulate in the esophagus and transfer experimental EoE. Expression of IL1RL1/ST2 mRNA was increased in esophageal biopsy specimens from patients with EoE. Topical OVA application on unstripped skin induced experimental EoE in filaggrin-deficient flaky tail (ft/ft) mice but not in wild-type control or ft/ft.St2-/-mice.
  
  
  
  Epicutaneous allergic sensitization promotes EoE, and this is critically mediated through the IL-33-ST2-basophil axis.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Venturelli
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Willem S
authors.initials: WS
authors.lastname: Lexmond
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass.
authors.forename: Asa
authors.initials: A
authors.lastname: Ohsaki
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Mass; Center for Motility and Functional Gastrointestinal Disorders, Boston Children's Hospital, Boston, Mass; Eosinophilic Gastrointestinal Disease Center, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Samuel
authors.initials: S
authors.lastname: Nurko
authors.affiliation: Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Karasuyama
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Edda
authors.initials: E
authors.lastname: Fiebiger
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: michiko.oyoshi@childrens.harvard.edu.
authors.forename: Michiko K
authors.initials: MK
authors.lastname: Oyoshi
mesh_terms: D000293:Adolescent; D000485:Allergens / Q000276:immunology; D000818:Animals; D001491:Basophils / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003876:Dermatitis, Atopic / Q000276:immunology*; D057765:Eosinophilic Esophagitis / Q000276:immunology*; D004947:Esophagus / Q000276:immunology; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D000067596:Interleukin-33 / Q000276:immunology*; D008297:Male; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology
chemical_list: D000485:Allergens; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C508590:IL1R1 protein, human; C506536:IL33 protein, human; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D010047:Ovalbumin
keywords: Basophils; IL-33; ST2; eosinophilic esophagitis; filaggrin; skin barrier