TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.
BACKGROUND
The pathogenesis of severe asthma in childhood remains poorly understood.


OBJECTIVE
We sought to construct the immunologic landscape in the airways of children with severe asthma.


METHODS
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.


RESULTS
Memory CCR5+ TH1 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 TH types, and BAL fluid CD8+ T cells were almost exclusively IFN-γ+. The TH17-associated mediators IL-23 and macrophage inflammatory protein 3α/CCL20 were highly expressed. Despite low TH2 numbers, TH2 cytokines were detected, and TH2 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.


CONCLUSIONS
The lower airways of children with severe asthma display a dominant TH1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of TH1 cells in patients with severe asthma.
['Wisniewski|Julia A|JA|', 'Muehling|Lyndsey M|LM|', 'Eccles|Jacob D|JD|', 'Capaldo|Brian J|BJ|', 'Agrawal|Rachana|R|', 'Shirley|Debbie-Ann|DA|', 'Patrie|James T|JT|', 'Workman|Lisa J|LJ|', 'Schuyler|Alexander J|AJ|', 'Lawrence|Monica G|MG|', 'Teague|W Gerald|WG|', 'Woodfolk|Judith A|JA|']
D000293:Adolescent D001249:Asthma D001992:Bronchoalveolar Lavage Fluid D002648:Child D002675:Child, Preschool D005260:Female D006801:Humans D006967:Hypersensitivity D007223:Infant D008168:Lung D008297:Male D018417:Th1 Cells
Severe asthma allergic IL-23 IgE type 2 innate lymphoid cells IL-5 IL-33 IL-28A IFN-γ IL-4 T(H)1 cells T(H)17 cells T(H)2 cells