title: Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma.
abstract: BACKGROUND
  The mechanism of TH2/TH17-predominant and TH2/TH17-low asthma is unknown.
  
  
  OBJECTIVE
  We sought to study the immune mechanism of TH2/TH17-predominant and TH2/TH17-low asthma.
  
  
  METHODS
  In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with TH2/TH17-predominant asthma and 22 patients with TH2/TH17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups.
  
  
  RESULTS
  Patients with TH2/TH17-predominant asthma had increased IL-1β, IL-6, IL-23, C3a, and serum amyloid A levels in BAL fluid, and these correlated with IL-1β and C3a levels. TH2/TH17 cells expressed higher levels of the IL-1 receptor and phospho-p38 mitogen-activated protein kinase. Anakinra, an IL-1 receptor antagonist protein, inhibited BAL TH2/TH17 cell counts. TH2/TH17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with TH2/TH17-predominant and TH2-predominant asthma, which included neutrophilic asthma in 6% and 0% of patients, respectively. BAL fluid neutrophils strongly correlated with BAL fluid myeloperoxidase, IL-8, IL-1α, IL-6, granulocyte colony-stimulating factor, and GM-CSF levels. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection.
  
  
  CONCLUSIONS
  We uncovered a critical role for the IL-1β pathway in patients with TH2/TH17-predminant asthma. A subgroup of patients with TH2/TH17-low asthma had neutrophilic asthma and increased BAL fluid IL-1α, IL-6, IL-8, granulocyte colony-stimulating factor, and GM-CSF levels. IL-1α was directly involved in IL-8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo.
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo.
authors.forename: Sucai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Verma
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo.
authors.forename: Iram
authors.initials: I
authors.lastname: Zafar
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo.
authors.forename: James T
authors.initials: JT
authors.lastname: Good
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo.
authors.forename: Donald
authors.initials: D
authors.lastname: Rollins
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo.
authors.forename: Stephen
authors.initials: S
authors.lastname: Groshong
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Gorska
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: Department of Medicine, Division of Allergy & Immunology, and Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo; School of Medicine, University of Colorado Denver, Denver, Colo. Electronic address: alamr@njhealth.org.
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D015926:Complement C3a / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D007958:Leukocyte Count; D008070:Lipopolysaccharides; D009504:Neutrophils / Q000276:immunology*; D000685:Serum Amyloid A Protein / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D000685:Serum Amyloid A Protein; D015926:Complement C3a; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Asthma endotype; C3a; IL-1; T(H)2/T(H)17-predominant asthma; infection; neutrophilic asthma