Human asthma phenotypes: from the clinic, to cytokines, and back again

Abstract

A large body of experimental evidence supports the hypothesis that T-helper 2 (Th2) cytokines orchestrate allergic airway inflammation in animal models. However, human asthma is heterogeneous with respect to clinical features, cellular sources of inflammation, and response to common therapies. This disease heterogeneity has been investigated using sputum cytology as well as unbiased clustering approaches using cellular and clinical data. Important differences in cytokine-driven inflammation may underlie this heterogeneity, and studies in human subjects with asthma have begun to elucidate these molecular differences. This molecular heterogeneity may be assessed by existing biomarkers (induced sputum evaluation or exhaled nitric oxide testing) or may require novel biomarkers. Effective testing and application of emerging therapies that target Th2 cytokines will depend on accurate and easily obtained biomarkers of this molecular heterogeneity in asthma. Furthermore, whether other non-Th2 cytokine pathways underlie airway inflammation in specific subsets of patients with asthma is an unresolved question and an important goal of future research using both mouse models and human studies.

Fig. 1. Expression levels of three IL-13 induced genes in the airway define two subgroups of asthmatics

(A) Heatmap depicting unsupervised hierarchical clustering (Euclidean complete) of POSTN, CLCA1, and SERPINB2 expression levels in bronchial epithelial brushings across 42 subjects with asthma (denoted by ‘A’) and 28 healthy controls (‘H’). (B) Mean (+ SEM) expression levels of IL-4, IL-5, and IL-13 in bronchial biopsy homogenates obtained contemporaneously with bronchial brushings from a subset of subjects depicted in Figure 1A (cluster 1: 18 ‘Th2-high’ asthmatics, red bars; cluster 2: 14 healthy controls, grey bars, and 16 ‘Th2-low’ asthmatics, blue bars). Two-way correlations across all subjects between IL-4, IL-5, and IL-13 indicated at right (Spearman’s rank correlation).

Fig. 2. Responsiveness of ‘Th2-high’ asthma to inhaled steroids in a randomized placebo-controlled trial

FEV₁ measured at baseline (week 0), after 4 and 8 weeks on daily fluticasone (500μg BID), and one week after the cessation of fluticasone (week 9). N=6 Th2-low on fluticasone (blue line), 10 Th2-high on fluticasone (red) and 11 on placebo (black). * denotes p<0.05 for comparison with placebo.