title: IL-33, but not thymic stromal lymphopoietin or IL-25, is central to mite and peanut allergic sensitization.
abstract: BACKGROUND
  Allergen exposure at lung and gut mucosae can lead to aberrant T(H)2 immunity and allergic disease. The epithelium-associated cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 are suggested to be important for the initiation of these responses.
  
  
  OBJECTIVE
  We sought to investigate the contributions of TSLP, IL-25, and IL-33 in the development of allergic disease to the common allergens house dust mite (HDM) or peanut.
  
  
  METHODS
  Neutralizing antibodies or mice deficient in TSLP, IL-25, or IL-33 signaling were exposed to HDM intranasally or peanut intragastrically, and immune inflammatory and physiologic responses were evaluated. In vitro assays were performed to examine specific dendritic cell (DC) functions.
  
  
  RESULTS
  We showed that experimental HDM-induced allergic asthma and food allergy and anaphylaxis to peanut were associated with TSLP production but developed independently of TSLP, likely because these allergens functionally mimicked TSLP inhibition of IL-12 production and induction of OX40 ligand (OX40L) on DCs. Blockade of OX40L significantly lessened allergic responses to HDM or peanut. Although IL-25 and IL-33 induced OX40L on DCs in vitro, only IL-33 signaling was necessary for intact allergic immunity, likely because of its superior ability to induce DC OX40L and expand innate lymphoid cells in vivo.
  
  
  CONCLUSIONS
  These data identify a nonredundant, IL-33-driven mechanism initiating T(H)2 responses to the clinically relevant allergens HDM and peanut. Our findings, along with those in infectious and transgenic/surrogate allergen systems, favor a paradigm whereby multiple molecular pathways can initiate T(H)2 immunity, which has implications for the conceptualization and manipulation of these responses in health and disease.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Chu
authors.forename: Alba
authors.initials: A
authors.lastname: Llop-Guevara
authors.forename: Tina D
authors.initials: TD
authors.lastname: Walker
authors.forename: Kristin
authors.initials: K
authors.lastname: Flader
authors.forename: Susanna
authors.initials: S
authors.lastname: Goncharova
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Boudreau
authors.forename: Cheryl Lynn
authors.initials: CL
authors.lastname: Moore
authors.forename: Tracy
authors.initials: T
authors.lastname: Seunghyun In
authors.forename: Susan
authors.initials: S
authors.lastname: Waserman
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.forename: Alison A
authors.initials: AA
authors.lastname: Humbles
authors.forename: Manel
authors.initials: M
authors.lastname: Jordana
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D010367:Arachis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D053278:OX40 Ligand / Q000276:immunology / Q000378:metabolism; D039981:Pyroglyphidae / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D000485:Allergens; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; C442281:Mydgf protein, mouse; D053278:OX40 Ligand; D011971:Receptors, Immunologic; D050800:STAT6 Transcription Factor; D015847:Interleukin-4