T-helper Type 2–driven Inflammation Defines Major Subphenotypes of Asthma

作者：Prescott G. Woodruff, Barmak Modrek, David F. Choy, Guiquan Jia, Alexander R. Abbas, Almut Ellwanger, Joseph R. Arron, Laura L. Koth, John V. Fahy · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2009 · DOI：10.1164/rccm.200903-0392oc · 被引用次数：1842 · 研究领域：Asthma and respiratory diseases、IL-33, ST2, and ILC Pathways、Dermatology and Skin Diseases

RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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 asth...