Abstract
Atopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced type 2-associated inflammation. However, the vast majority of atopics do not develop asthma despite ongoing aeroallergen exposure, suggesting additional mechanisms operate in conjunction with type 2 immunity to drive asthma pathogenesis. We employed RNA-Seq profiling of sputum-derived cells to identify gene networks operative at baseline in house dust mite-sensitized (HDMS) subjects with/without wheezing history that are characteristic of the ongoing asthmatic state. The expression of type 2 effectors (IL-5, IL-13) was equivalent in both cohorts of subjects. However, in HDMS-wheezers they were associated with upregulation of two coexpression modules comprising multiple type 2- and epithelial-associated genes. The first module was interlinked by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3 and mucociliary clearance genes. Our findings provide new insight into the molecular mechanisms operative at baseline in the airway mucosa in atopic asthmatics undergoing natural aeroallergen exposure, and suggest that susceptibility to asthma amongst these subjects involves complex interactions between type 2- and epithelial-associated gene networks, which are not operative in equivalently sensitized/exposed atopic non-asthmatics.
Highlights
Asthma is a chronic disease of the conducting airways that is characterized by episodic airways inflammation, airways remodeling, and progressive loss of lung function
Our findings suggest that upregulation of type 2 signature genes exemplified by the effector cytokines IL-5 and IL-13 is a common feature across the whole house dust mite-sensitized (HDMS)/exposed population at baseline, but in the subgroup with history of current wheeze the type 2 signature is more complex, and is uniquely networked with a series of concomitantly upregulated epithelial cell associated pathways
The specific focus of this study is asthma in young adult atopics who are highly sensitized to house dust mite (HDM) allergen
Summary
Asthma is a chronic disease of the conducting airways that is characterized by episodic airways inflammation, airways remodeling, and progressive loss of lung function. The degree to which chronic exposure to type 2-stimulatory perennial aeroallergens contributes to the inflammatory milieu in the airway mucosa of sensitized atopics during the periods between overt exacerbation events, potentially influencing long-term persistence of the asthma-associated wheezy phenotype, remains unclear, and this question was the focus of this investigation. Resolving this issue is important in relation to design of future therapeutic strategies for prevention of asthma progression i.e. is it sufficient to target severe exacerbation events alone, or is it potentially necessary to dampen ongoing aeroallergen-driven type 2 reactivity at baseline in sensitized/perennially exposed subjects?. Our findings suggest that upregulation of type 2 signature genes exemplified by the effector cytokines IL-5 and IL-13 is a common feature across the whole HDMS/exposed population at baseline, but in the subgroup with history of current wheeze the type 2 signature is more complex, and is uniquely networked with a series of concomitantly upregulated epithelial cell associated pathways
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