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

Susana Castanhinha, Rebekah Sherburn, Simone Walker, Atul Gupta, Cara J. Bossley, James Buckley, Nicola Ullmann, Ruth Grychtol, Gaynor Campbell, Marco Maglione, Sergio Koo, Louise Fleming, Lisa Gregory, Robert J. Snelgrove, Andrew Bush, Clare M. Lloyd, Sejal Saglani

Research output: Contribution to journalArticle

93 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)312-322.e7
JournalJournal of Allergy and Clinical Immunology
Volume136
Issue number2
DOIs
Publication statusPublished - Aug 1 2015

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Asthma
Steroids
Pediatrics
Immunoglobulin E
Interleukin-13
Cell Count
Pyroglyphidae
Interleukin-33
Lymphocytes
Cladosporium
Budesonide
Alternaria
Lung
Aspergillus fumigatus
Therapeutics
Skin Tests
Allergens
Fungi
Maintenance
Serum

Keywords

  • fungal sensitization
  • IL-33
  • innate immunity
  • pediatric
  • Severe asthma
  • steroid resistance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Castanhinha, S., Sherburn, R., Walker, S., Gupta, A., Bossley, C. J., Buckley, J., ... 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. https://doi.org/10.1016/j.jaci.2015.01.016

Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. / Castanhinha, Susana; Sherburn, Rebekah; Walker, Simone; Gupta, Atul; Bossley, Cara J.; Buckley, James; Ullmann, Nicola; Grychtol, Ruth; Campbell, Gaynor; Maglione, Marco; Koo, Sergio; Fleming, Louise; Gregory, Lisa; Snelgrove, Robert J.; Bush, Andrew; Lloyd, Clare M.; Saglani, Sejal.

In: Journal of Allergy and Clinical Immunology, Vol. 136, No. 2, 01.08.2015, p. 312-322.e7.

Research output: Contribution to journalArticle

Castanhinha, S, Sherburn, R, Walker, S, Gupta, A, Bossley, CJ, Buckley, J, 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, vol. 136, no. 2, pp. 312-322.e7. https://doi.org/10.1016/j.jaci.2015.01.016
Castanhinha, Susana ; Sherburn, Rebekah ; Walker, Simone ; Gupta, Atul ; Bossley, Cara J. ; Buckley, James ; Ullmann, Nicola ; Grychtol, Ruth ; Campbell, Gaynor ; Maglione, Marco ; Koo, Sergio ; Fleming, Louise ; Gregory, Lisa ; Snelgrove, Robert J. ; Bush, Andrew ; Lloyd, Clare M. ; Saglani, Sejal. / Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 136, No. 2. pp. 312-322.e7.
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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.",
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AU - Castanhinha, Susana

AU - Sherburn, Rebekah

AU - Walker, Simone

AU - Gupta, Atul

AU - Bossley, Cara J.

AU - Buckley, James

AU - Ullmann, Nicola

AU - Grychtol, Ruth

AU - Campbell, Gaynor

AU - Maglione, Marco

AU - Koo, Sergio

AU - Fleming, Louise

AU - Gregory, Lisa

AU - Snelgrove, Robert J.

AU - Bush, Andrew

AU - Lloyd, Clare M.

AU - Saglani, Sejal

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N2 - 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.

AB - 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.

KW - fungal sensitization

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KW - innate immunity

KW - pediatric

KW - Severe asthma

KW - steroid resistance

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