title: Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice.
abstract: We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: L M
authors.initials: LM
authors.lastname: Judd
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia; Department of Allergy and Immunology, The Royal Children's Hospital, Parkville, Victoria, Australia; Department of Gastroenterology and Clinical Nutrition, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: R G
authors.initials: RG
authors.lastname: Heine
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: T R
authors.initials: TR
authors.lastname: Menheniott
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: J
authors.initials: J
authors.lastname: Buzzelli
authors.affiliation: Oral Health Cooperative Research Center, Melbourne Dental School, University of Melbourne, Parkville, Victoria, Australia; and.
authors.forename: N
authors.initials: N
authors.lastname: O'Brien-Simpson
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: D
authors.initials: D
authors.lastname: Pavlic
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: L
authors.initials: L
authors.lastname: O'Connor
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: K
authors.initials: K
authors.lastname: Al Gazali
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: O
authors.initials: O
authors.lastname: Hamilton
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: M
authors.initials: M
authors.lastname: Scurr
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Collison
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Mattes
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia; Department of Allergy and Immunology, The Royal Children's Hospital, Parkville, Victoria, Australia; Department of Gastroenterology and Clinical Nutrition, The Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: K J
authors.initials: KJ
authors.lastname: Allen
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia; andrew.giraud@mcri.edu.au.
authors.forename: A S
authors.initials: AS
authors.lastname: Giraud
mesh_terms: D056704:Adaptive Immunity; D000293:Adolescent; D000818:Animals; D001232:Aspergillus fumigatus / Q000472:pathogenicity; D001706:Biopsy; D016022:Case-Control Studies; D049109:Cell Proliferation; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D057765:Eosinophilic Esophagitis / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D004947:Esophagus / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism*; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; C506536:IL33 protein, human; C506535:Il33 protein, mouse; D018836:Inflammation Mediators; D018793:Interleukin-13; D000067596:Interleukin-33; D012333:RNA, Messenger
keywords: IL-33; Th2; eosinophilic esophagitis; food allergy