Abstract
Rationale: Gene signatures (GSs) of inflammatory pathways can be used to stratify out asthma patients to identify novel clinical phenotypes. Literature suggests the existence of an asthma phenotype defined by TH2/ IL-33 activation, however this is poorly understood. Identification of a gene signature of the IL-33-driven changes in the TH2 cell transcriptome can be used to probe asthma omics and clinical data to elucidate this phenotype.
Methods: CD4+ T cells were isolated from healthy control and asthma airway wall for single-cell sequencing. Differentiated TH2 cells from PBMCs were stimulated using anti-CD3/CD28 in the presence or absence of IL-33 and RNA-sequenced. Differentially expressed genes (DEGs) between stimulated and non-stimulated cells defined an IL-33-stimulated TH2 cell GS. This was used to probe blood and airway omics of the U-BIOPRED cohort through GSVA analysis.
Results: 3699 DEGs were induced by IL-33 stimulation affecting up to 40% of the transcriptomic changes in TH2 cell activation. However, genes with highest fold induction had lowest baseline expression and were sparsely detected in cell-type specific datasets. Hence, based on the baseline gene expression and log fold change (LFC), the genes were segregated into 4 quartiles to make 4 GSs. In U-BIOPRED sputum transcriptomics data, the upper quartile GS was elevated in the pauci-granulocytic asthma phenotype and had a strong positive correlation with sputum macrophages and lymphocytes.
Conclusions: An IL-33-stimulated TH2 GS indicates pauci-granulocytic asthma as being driven by TH2/ IL-33 activation. Here we present a novel method of generating GSs through fold induction selection of genes with low baseline expression.
Footnotes
Cite this article as ERJ Open Research 2022; 8: Suppl. 8, 114.
This article was presented at the 2022 ERS Lung Science Conference, in session “Poster Session 2”.
This is an ERS Lung Science Conference abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2022