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Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33.

Castanhinha, S; Sherburn, R; Walker, S; Gupta, A; Bossley, CJ; Buckley, JS; Ullmann, N; Grychtol, R; Campbell, G; Maglione, M; et al. Castanhinha, S; Sherburn, R; Walker, S; Gupta, A; Bossley, CJ; Buckley, JS; Ullmann, N; Grychtol, R; Campbell, G; Maglione, M; Koo, S; Fleming, L; Gregory, L; Snelgrove, RJ; Bush, A; Lloyd, CM; Saglani, S (2015) Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. Journal of Allergy and Clinical Immunology, 136 (2). 312-322.e7. ISSN 1097-6825 https://doi.org/10.1016/j.jaci.2015.01.016
SGUL Authors: Buckley, James Samuel

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Abstract

Background The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. Objective We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. Methods Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. Results Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2−/− mice lacking a functional receptor for IL-33. Conclusion Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33–mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.

Item Type: Article
Additional Information: © 2015 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Allergy, 1107 Immunology
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Journal of Allergy and Clinical Immunology
ISSN: 1097-6825
Dates:
DateEvent
August 2015Published
5 March 2015Published Online
5 January 2015Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
086718/Z/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
095707/Z/11/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
MR/J010529/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
GR 4379/1 1German Research FoundationUNSPECIFIED
URI: https://openaccess.sgul.ac.uk/id/eprint/110026
Publisher's version: https://doi.org/10.1016/j.jaci.2015.01.016

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