Mechanisms of allergy and clinical immunology
IL-33, but not thymic stromal lymphopoietin or IL-25, is central to mite and peanut allergic sensitization

https://doi.org/10.1016/j.jaci.2012.08.002Get rights and content

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.

Section snippets

Methods

Supplemental information can be found in the Methods section in this article’s Online Repository at www.jacionline.org.

Airway sensitization to HDM does not require TSLP signaling

We sought to investigate the requirement of TSLP in experimental allergic asthma to the clinically relevant allergen HDM. This model23 solely involves mucosal exposure, does not use any exogenous adjuvant, and critically requires the canonical TH2-inducing molecule IL-4.24 Consistent with a previous report,25 TSLP was detected in the lungs of naive mice, and levels were increased upon 3-day HDM exposure (Fig 1, A), a protocol that induces sensitization without overt inflammation. TSLP

Discussion

It has been increasingly recognized that TH2 immunity results from adaptive immune responses that are shaped by initial innate signals. Among these, epithelium-associated cytokines, such as TSLP, IL-25, and IL-33, have been the subject of intense investigation. Here we investigated the initiation of allergic asthma and food allergy using models involving 2 clinically relevant allergens and different mucosal sites and sensitization strategies. We show that the development of HDM and peanut

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    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.

    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.

    These authors contributed equally to this work.

    Jeanette E. Boudreau, PhD, is currently affiliated with the Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY.

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