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

¹ Division of Pulmonary and Critical Care Medicine and ² Cardiovascular Research Institute, Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; ³ Department of Bioinformatics and ⁴ ITGR Biomarker Group, Genentech, Inc., South San Francisco, California; and ⁵ Lung Biology Center, Department of Medicine, Cardiovascular Research Institute, University of San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Prescott G. Woodruff, M.D., M.P.H., 505 Parnassus Ave, M1098, Box 0111, San Francisco, CA 94143-0111. E-mail: Prescott.woodruff{at}ucsf.edu

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 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.

Key Words: asthma • phenotypes • inflammation • airway remodeling

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Clinical studies increasingly suggest that asthma is heterogeneous, but the molecular basis for this heterogeneity is uncertain. What This Study Adds to the Field This study suggests that asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Therapies targeting Th2 cytokines may be effective in only a subset of patients with asthma. Non–Th2-driven asthma represents a significant proportion of patients and responds poorly to current therapies.

 

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