Resumen
Background: Allergen exposure at lung and gut mucosae can lead to aberrant TH2 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. Conclusion: These data identify a nonredundant, IL-33-driven mechanism initiating TH2 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 TH2 immunity, which has implications for the conceptualization and manipulation of these responses in health and disease.
Idioma original | English |
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Páginas (desde-hasta) | 187-200e8 |
Publicación | Journal of Allergy and Clinical Immunology |
Volumen | 131 |
N.º | 1 |
DOI | |
Estado | Published - ene. 2013 |
Publicado de forma externa | Sí |
Nota bibliográfica
Funding Information:Disclosure of potential conflict of interest: S. Waserman has received research support from Anaphylaxis Canada and is employed by McMaster University. A. J. Coyle was an employee of MedImmune LLC and is now an employee of Pfizer. R. Kolbeck is employed by and has stock options in MedImmune LLC. A. A. Humbles is employed by MedImmune LLC and has stock options in MedImmune (AZ). M. Jordana has received research support from MedImmune LLC, Anaphylaxis Canada, and the Canadian Institutes of Health Research and is employed by McMaster University. The rest of the authors declare that they have no relevant conflicts of interest.
Funding Information:
Supported by CIHR, Anaphylaxis Canada , and grants from MedImmune LLC . D.K.C. is a CIHR Vanier Scholar. A.L.-G. is supported by a Fundación Caja Madrid doctoral scholarship (Spain). J.E.B. holds an NSERC Doctoral Canada Graduate Scholarship. M.J. holds a Senior Canada Research Chair in Immunobiology of Respiratory Diseases and Allergy.
ASJC Scopus Subject Areas
- Immunology and Allergy
- Immunology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't