title: β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses.
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.
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Biagini Myers
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Brandt
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Ryan
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Mark
authors.initials: M
authors.lastname: Lindsey
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Mintz-Cole
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Tiina
authors.initials: T
authors.lastname: Reponen
authors.affiliation: Environmental Protection Agency, Cincinnati, Ohio.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Vesper
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Frank
authors.initials: F
authors.lastname: Forde
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Brandy
authors.initials: B
authors.lastname: Ruff
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Bass
authors.affiliation: 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.
authors.forename: Grace K
authors.initials: GK
authors.lastname: LeMasters
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: James
authors.initials: J
authors.lastname: Lockey
authors.affiliation: Department of Inflammation Research, Amgen, Seattle, Wash.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky
authors.affiliation: 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: Gurjit.Hershey@cchmc.org.
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Khurana Hershey
mesh_terms: D000393:Air Pollutants / Q000276:immunology; D000485:Allergens / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000627:therapeutic use; D004351:Drug Resistance / Q000276:immunology; D004781:Environmental Exposure; D005260:Female; D005658:Fungi / Q000276:immunology*; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D020381:Interleukin-17 / Q000097:blood / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015995:Prevalence; D018123:Receptors, Interleukin / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D047071:beta-Glucans / Q000276:immunology*; D000099181:Dectin-1
chemical_list: D000393:Air Pollutants; D000485:Allergens; D000893:Anti-Inflammatory Agents; D039741:Antigens, Dermatophagoides; D003907:Dexamethasone; D005938:Glucocorticoids; D020381:Interleukin-17; D037181:Lectins, C-Type; D018123:Receptors, Interleukin; D047071:beta-Glucans; D000099181:Dectin-1; C508717:IL17A protein, human; C508527:Il17rc protein, mouse
keywords: Childhood asthma; IL-17A; allergy; fungal exposure; fungi; house dust mite; β-glucan