Background

Type 2 (T2) inflammation drives airway dysfunction in many patients with asthma; yet, we lack a comprehensive understanding of the airway immune cell types and networks that sustain this inflammation. Moreover, defects in the airway immune system in patients with asthma without T2 inflammation are not established.

Objectives

To determine the gene networks that sustain T2 airway inflammation in T2-high asthma and to explore the gene networks that characterize T2-low asthma.

Methods

Network analysis of sputum cell transcriptome expression data from 84 subjects with asthma and 27 healthy control subjects was used to identify immune cell type-enriched networks that underlie asthma subgroups.

Results

Sputum T2 gene expression was characterized by an immune cell network derived from multiple innate immune cells, including eosinophils, mast cells/basophils, and inflammatory dendritic cells. Clustering of subjects within this network stratified subjects into T2-high and T2-low groups, but it also revealed a subgroup of T2-high subjects with uniformly higher expression of the T2 network. These "T2-ultrahigh subjects" were characterized clinically by older age and more severe airflow obstruction and pathologically by a second T2 network derived from T2-skewed, CD11b⁺/CD103^-/IRF4⁺ classical dendritic cells. Subjects with T2-low asthma were differentiated from healthy control subjects by lower expression of a cytotoxic CD8⁺ T-cell network, which was negatively correlated with body mass index and plasma IL-6 concentrations.

Conclusions

Persistent airway T2 inflammation is a complex construct of innate and adaptive immunity gene expression networks that are variable across individuals with asthma and persist despite steroid treatment. Individuals with T2-low asthma exhibit an airway deficiency in cytotoxic T cells associated with obesity-driven inflammation.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC⁺ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.