T-helper type 2-driven inflammation defines major subphenotypes of asthma.
By P. Woodruff, Barmak Modrek, D. Choy, G. Jia, Alexander R. Abbas, A. Ellwanger, L. Koth, J. Arron, J. Fahy. American Journal of Respiratory and Critical Care Medicine, 2009
1,732 citations recorded by the source corpus.
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.
Subfields: Dermatology, Immunology, Physiology
View Paper: https://www.semanticscholar.org/paper/2223f49fb3be08402f0033db0f41419ec3784f13
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Citations in the corpus
- Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease (2018, neutral): “T2-biased airway inflammation is observed in only half of patients with asthma [61] and only in 37% of patients”
- International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma (2013, background): “While the eosinophilic or ‘Th-2 high’ asthma phenotype, characterized by high expression of Th2 cytokines, IL-5 and IL-13, identifies inhaled CS responsiveness in patients with milder asthma, eosinophilic inflammation may persist in some severe asthma patients despite high dose ICS, and even systemi”