T_H1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.

Abstract

The pathogenesis of severe asthma in childhood remains poorly understood. We sought to construct the immunologic landscape in the airways of children with severe asthma. Comprehensive analysis of multiple cell types and mediators was performed by using flow cytometry and a multiplex assay with bronchoalveolar lavage (BAL) specimens (n = 68) from 52 highly characterized allergic and nonallergic children (0.5-17 years) with severe treatment-refractory asthma. Multiple relationships were tested by using linear mixed-effects modeling. Memory CCR5⁺ T_H1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ⁺IL-17⁺ and IFN-γ^-IL-17⁺ subsets constituted secondary T_H types, and BAL fluid CD8⁺ T cells were almost exclusively IFN-γ⁺. The T_H17-associated mediators IL-23 and macrophage inflammatory protein 3α/CCL20 were highly expressed. Despite low T_H2 numbers, T_H2 cytokines were detected, and T_H2 skewing correlated with total IgE levels. Type 2 innate lymphoid cells and basophils were scarce in BAL fluid. Levels of IL-5, IL-33, and IL-28A/IFN-λ2 were increased in multisensitized children and correlated with IgE levels to dust mite, ryegrass, and fungi but not cat, ragweed, or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE⁺FcεRI⁺ myeloid dendritic cells were present in BAL fluid. The lower airways of children with severe asthma display a dominant T_H1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of T_H1 cells in patients with severe asthma.