Dataset Information

TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.

ABSTRACT: 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-?+IL-17+ and IFN-?-IL-17+ subsets constituted secondary TH types, and BAL fluid CD8+ T cells were almost exclusively IFN-?+. The TH17-associated mediators IL-23 and macrophage inflammatory protein 3?/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-?2 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+Fc?RI+ 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.

SUBMITTER: Wisniewski JA

PROVIDER: S-EPMC5860937 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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T<sub>H</sub>1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.

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

The Journal of allergy and clinical immunology 20170920 6

<h4>Background</h4>The pathogenesis of severe asthma in childhood remains poorly understood.<h4>Objective</h4>We sought to construct the immunologic landscape in the airways of children with severe asthma.<h4>Methods</h4>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-refrac ...[more]

PMID: 28939412

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Project description:Background: This differential diagnosis of allergic vs non-allergic asthma is typically made on the basis of sensitization to allergens, such that absence of sensitization could result in a patient being managed as having non-allergic asthma. In Germany, the number of specific allergen tests is limited and non-standardized (across clinicians and laboratories), with the potential for false negative diagnoses. IDENTIFY aimed to gain data on sensitizations toward aeroallergens in patients with severe asthma who had tested negative to perennial aeroallergens in previous tests.Methods: This was a single visit, non-randomized, non-interventional study conducted in 87 centers across Germany. The only inclusion criteria were that patients had to be adults (at least 18 years of age) with a diagnosis of severe asthma (receiving at least Global Initiative for Asthma Step IV therapy), and who had previously tested negative to perennial aeroallergens. Patients were then tested for sensitization to a panel of 35 perennial aeroallergens, with positive sensitization indicated by CAP???0.35 kU/L.Results: Of 588 patients recruited, 454 had complete and valid data, and had previously tested negative to perennial aeroallergens. Overall, 43.6% of the analyzed patients tested positive for at least one of the included aeroallergens, with 18.7% testing positive for three or more, and 4.2% positive for more than ten. The five most common sensitizations were to Staphylococcus aureus enterotoxin B, Aspergillus fumigatus, Candida albicans, Dermatophagoides farinae, and Rhizopus nigricans, each of which tested positive in at least 9.7% of the population.Conclusions: In this group of patients being managed as having non-allergic asthma (and who had all previously tested negative to perennial aeroallergens), a high proportion tested positive to a broad panel of aeroallergens. A diagnosis of allergic asthma therefore cannot be excluded purely on the basis of standard aeroallergen panels.

Project description:BackgroundAllergic rhinitis (AR) is an important risk factor for the development of asthma. The "unified airway" theory considers the upper and lower airways as a morphological and functional whole. However, studies exploring biomarkers linking the upper and lower airways in allergic disease are lacking, which may provide insight into the mechanisms underlying AR comorbid asthma.PurposeTo integrate bioinformatics techniques to explore biomarkers in airway allergic diseases, and to provide a molecular etiology profile for preventing the development of asthma in AR patients.MethodsBiomarkers were screened by identifying key genes common between AR and asthma through WGCNA and differential gene analysis. GO and KEGG analyses were performed using DAVID. Immuno-infiltration analysis was performed by CIBERSORTx. The predictive value of CST1 to distinguish Th2-high asthma was determined by ROC curves. GSEA was used to analyze the signaling pathways involved in CST1. TargetScan and miRNet were combined with GSE142237 to construct ceRNA network. CMap was used to explore potential therapeutic drugs.ResultsValidation of datasets showed that CST1 was the only gene that was up-regulated in both upper and lower airways in patients with AR and asthma, and correlation heatmaps showed that CST1 was the gene with the highest sum of correlation coefficients. GO and KEGG analysis demonstrated that the lower airways of AR patients were mainly involved in inflammatory and immune responses, similar to asthma. Immune infiltration showed that CST1 was mainly positively correlated with activated CD4 memory T cells. According to the ROC curve, CST1 showed excellent diagnostic efficiency for Th2-high asthma. GSEA indicated that CST1 was involved in the FcϵRI signaling pathway and O-glycan biosynthesis. A ceRNA network including the lncRNAs KCNQ1OT1 and NEAT1 was constructed. Four drugs, including verrucarin-A, had the potential to prevent the development of asthma in AR patients. In addition, corticosteroids were found to downregulate CST1 expression.ConclusionCST1 plays a key role in the development of AR comorbid asthma and may be a biomarker for airway allergic diseases. Targeted treatment of CST1 has the potential to prevent the development of asthma in AR patients and deserves further study.

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TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.

Publications

T<sub>H</sub>1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.

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