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

TLDR

Asthma is driven by Th2 inflammation mediated by IL‑4, IL‑5, and IL‑13, yet clinical studies reveal heterogeneity that current models fail to explain, especially for non‑Th2‑driven disease. The study aims to determine whether asthma heterogeneity reflects differences in underlying Th2‑related molecular mechanisms. The authors classified asthma patients by high or low IL‑13‑inducible gene expression using airway epithelial microarray and PCR, then validated the groups and examined cytokine profiles, inflammation markers, remodeling, steroid responsiveness, and reproducibility. Two distinct subgroups, Th2‑high and Th2‑low, were identified; Th2‑high patients exhibited higher IL‑5/IL‑13, airway hyperresponsiveness, IgE, eosinophilia, fibrosis, mucin expression, and steroid‑responsive lung function, whereas Th2‑low resembled controls, indicating Th2 cytokines are a therapeutic target only for a subset.

Abstract

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.To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation.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.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.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.