Th2 molecular phenotypes defined for severe asthma
medwireNews: Researchers have defined three molecular phenotypes of asthma, based on T-helper cell type 2 (Th2) status, which could help better target specific treatments.
The team obtained transcriptomic data from sputum cells supplied by 104 patients with moderate-to-severe asthma and 16 individuals without asthma from the Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort.
They used a clustering approach to analyze 508 differentially expressed genes from three pairwise comparisons of gene expression in the sputum cells of asthma patients with high eosinophil (EOS) counts, of at least 1.5%, patients with low EOS counts (non-EOS) below 1.5%, and controls.
Three distinct transcriptome-associated clusters (TAC) were identified from hierarchical clustering and resampling. TAC1 was a predominantly eosinophilic cluster with high activation of interleukin (IL)-13/Th2 and innate lymphoid cell type 2 (ILC2) gene signatures. TAC2 and TAC3, by contrast, were non-Th2 phenotypes characterized by interferon and tumor necrosis factor-α superfamily and inflammasome-associated genes in the case of TAC2, and metabolic, ubiquitination, and mitochondrial pathway genes in the case of TAC3.
TAC1 included exclusively patients with severe asthma and higher levels of oral corticosteroid dependency experiencing acute exacerbation, nasal polyps, and severe airflow obstruction, whereas TAC2 patients had the highest sputum neutrophil counts and C-reactive protein levels, and chronic airflow obstruction but had less severe asthma than patients in TAC1. TAC3 patients had normal to moderately high sputum eosinophil levels but better preserved forced expiratory volume in 1 second than the other groups, and were the least likely to be dependent on oral corticosteroids.
While eosinophilic inflammation was predominantly found in TAC1, as to be expected, it was also significantly present in TAC3. Neutrophilic inflammation was mainly found in TAC2 and TAC3 and the paucigranulocytic phenotype was primarily associated with TAC3.
Patients with mixed granulocytic asthma could fall either in the TAC1 or TAC2 category, with the former showing increased enrichment of IL-13/Th2 and the latter enriched for neutrophil and inflammasome signatures, the researchers note in the European Respiratory Journal.
The team, led by Kian Fan Chung (Imperial College London, UK), reports high co-expression of gene signatures with the corresponding protein signature in TAC1 and TAC2, suggesting similar levels of linked transcription–translation in each. This also revealed potential gene and protein biomarkers to target with treatment.
In TAC1, IL33R/ARSB, IL33R/PAPPA, and CLC/PAPPA were highly co-expressed, emphasizing the link between IL-33R and eosinophil activation markers, say the researchers. In the TAC2 subtype, IFITM3/PGLYRP1, IFITM1/PGLYRP1, and MEFV/PLCG1 were highly co-expressed, reflecting innate host defense responses to viruses and bacteria.
The gene–protein relationships in TAC3, on the other hand, were random and suggested diverse mechanisms were at play, predominantly post-transcriptional modifications and altered metabolic enzyme activity.
Alberto Papi (University of Ferrara, Italy) and colleagues comment in a related editorial that the significant overlap in Th2 and T-helper cell type 1 gene signatures even within clusters points to multiple activation by genetic signals.
They say that there is the potential for multiplicity of genetic signals to be coordinated by “master regulators” to make proteins work together to produce a complex effect on multiple target cells.
“It could be speculated that multiple pathogenic pathways could be triggered by the so-called master regulators that could direct asthma cell behaviour, as they might do in cancer, and provide the starting point for a different approach to drug development,” the editorialists comment.
By Lucy Piper
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