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β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses.

Authors
  • Zhang, Zhonghua1
  • Biagini Myers, Jocelyn M1
  • Brandt, Eric B1
  • Ryan, Patrick H2
  • Lindsey, Mark1
  • Mintz-Cole, Rachael A1
  • Reponen, Tiina3
  • Vesper, Stephen J4
  • Forde, Frank1
  • Ruff, Brandy1
  • Bass, Stacey A1
  • LeMasters, Grace K5
  • Bernstein, David I6
  • Lockey, James3
  • Budelsky, Alison L7
  • Khurana Hershey, Gurjit K8
  • 1 Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • 2 Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • 3 Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • 4 Environmental Protection Agency, Cincinnati, Ohio.
  • 5 Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • 6 Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • 7 Department of Inflammation Research, Amgen, Seattle, Wash.
  • 8 Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: [email protected]
Type
Published Article
Journal
The Journal of allergy and clinical immunology
Publication Date
Jan 01, 2017
Volume
139
Issue
1
Identifiers
DOI: 10.1016/j.jaci.2016.02.031
PMID: 27221135
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Allergic sensitization to fungi has been associated with asthma severity. As a result, it has been largely assumed that the contribution of fungi to allergic disease is mediated through their potent antigenicity. We sought to determine the mechanism by which fungi affect asthma development and severity. We integrated epidemiologic and experimental asthma models to explore the effect of fungal exposure on asthma development and severity. We report that fungal exposure enhances allergen-driven TH2 responses, promoting severe allergic asthma. This effect is independent of fungal sensitization and can be reconstituted with β-glucan and abrogated by neutralization of IL-17A. Furthermore, this severe asthma is resistant to steroids and characterized by mixed TH2 and TH17 responses, including IL-13+IL-17+CD4+ double-producing effector T cells. Steroid resistance is dependent on fungus-induced TH17 responses because steroid sensitivity was restored in IL-17rc-/- mice. Similarly, in children with asthma, fungal exposure was associated with increased serum IL-17A levels and asthma severity. Our data demonstrate that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. Furthermore, our results provide a strong rationale for combination treatment strategies targeting IL-17A for this subgroup of fungus-exposed patients with difficult-to-treat asthma. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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