title: T-helper type 2-driven inflammation defines major subphenotypes of asthma.
abstract: BACKGROUND
  T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous.
  
  
  OBJECTIVE
  To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation.
  
  
  METHODS
  Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination.
  
  
  RESULTS
  Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation.
  
  
  CONCLUSIONS
  Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA 94143-0111, USA. Prescott.woodruff@ucsf.edu
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.forename: Barmak
authors.initials: B
authors.lastname: Modrek
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.forename: Guiquan
authors.initials: G
authors.lastname: Jia
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Abbas
authors.forename: Almut
authors.initials: A
authors.lastname: Ellwanger
authors.forename: Laura L
authors.initials: LL
authors.lastname: Koth
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage; D001249:Asthma / Q000145:classification / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000473:pathology; D001993:Bronchodilator Agents / Q000008:administration & dosage; D005260:Female; D000068298:Fluticasone; D018740:Genetic Heterogeneity; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D009077:Mucins / Q000378:metabolism; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000473:pathology; D020545:Respiratory Mucosa / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D015415:Biomarkers; D001993:Bronchodilator Agents; D009077:Mucins; D000068298:Fluticasone