{
  "abstract": "Background Severe asthma is a heterogeneous disease. The mechanisms underlying airway inflammation, particularly when type 2 (T2) cytokine activity is suppressed, remain poorly understood. This study aimed to identify the airways molecular pathways of T2 biomarker-high and biomarker-low severe asthma under biomarker-based optimised corticosteroid therapy.Methods We analysed clinical data and transcriptomic data from the bronchial brushings and biopsies in the RASP-UK multi-centre severe asthma cohort. We included 18 corticosteroid-resistant T2 biomarker-high (T2-high), 23 corticosteroid-responsive T2 biomarker-intermediate (T2-intermediate) and 11 T2 biomarker-low (T2-low) patients with severe asthma and 20 healthy controls pre- and post-treatment with inhaled corticosteroids.Results Severe asthma, independent of confounding by therapeutic corticosteroids, was characterised by upregulation of mucins ( MUC5AC, MUC2), lysozyme, CEACAM5, SYNCRIP, typical T2-genes (POSTN, IL33), the transcription factor FOS, and ITGB8, which regulates TGFβ activation and airway remodelling. FeNO and blood eosinophils share many common transcriptome signatures, such as CCL26 and MMP1. However, some genes were associated only with eosinophils (e.g., EDN2) or FeNO (e.g., POSTN, CST1). Clinically, patients with T2-high asthma exhibited poorer pulmonary function, while those with T2-low asthma had an earlier disease onset, higher serum IgE levels, and experienced more frequent severe exacerbations. At the molecular level, T2-high asthma showed upregulation of T2-dependent genes, keratins, adaptive immune response, impaired ciliary function, and epithelial development. T2-low asthma was marked by upregulation of Th1- and Th17-associated genes (IDO1, CXCL10, GBP1, LAG3), neuroimmune genes (SGC2, CALCA), interferon-γ signalling, antigen processing, and enrichment of neutrophils and mast cells. T2-intermediate asthma exhibited a mixed molecular profile, sharing features of both T2-high and T2-low endotypes. It was characterised by expression of the antimicrobial peptide BPIFA1, viral response signatures, mast and natural killer (NK) cell enrichment, and activation of transcription factors involved in pathogen defence (NFKB1, TBX21, IRF1, IRF2, BATF, STAT2). This group also showed heightened immune responses, impaired mitochondrial function, and enhanced antigen processing pathways.Abstract S105 Figure 1Heatmap of gene cluster expression patterns across T2-high, -intermediate, and -low asthma. Heatmap of gene cluster expression patterns across T2-high, -intermediate, and -low asthma. Genes were grouped into distinct co-expression clusters (C1-C6) using k-means clustering based on shared expression profiles. Line plots to left show average expression profile of each gene cluster across phenotypes. Heatmap displays Z-score-normalized gene expression values with rows corresponding to genes and columns grouped by phenotype. Red indicates higher expression and blue indicates lower expression. Top enriched Gene Ontology (GO) biological process terms for each cluster are shown to right. Coloured bars reflect statistical significance of enrichmentConclusions This study delineates distinct molecular signatures and pathways in three major severe asthma phenotypes, independent of corticosteroid effects. These findings offer insights for personalised asthma management and the development of targeted biologic therapies.On behalf of the RASP-UK.",
  "authors": [
    {
      "affiliations": [
        "NIHR Oxford Respiratory BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "J Shen"
    },
    {
      "affiliations": [
        "Institute of Infection and Immunity, University of Glasgow, Glasgow, UK"
      ],
      "name": "R Chaudhuri"
    },
    {
      "affiliations": [
        "Institute of Infection and Immunity, University of Glasgow, Glasgow, UK"
      ],
      "name": "S Bicknell"
    },
    {
      "affiliations": [
        "University of Birmingham and Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"
      ],
      "name": "A Mansur"
    },
    {
      "affiliations": [
        "NIHR Oxford Respiratory BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "R Shrimanker"
    },
    {
      "affiliations": [
        "NIHR Oxford Respiratory BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "I Pavord"
    },
    {
      "affiliations": [
        "School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre and NIHR Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"
      ],
      "name": "S Fowler"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson- Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK"
      ],
      "name": "V Brown"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson- Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK"
      ],
      "name": "L McGarvey"
    },
    {
      "affiliations": [
        "School of Clinical and Experimental Sciences, University of Southampton, NIHR Southampton Biomedical Research Centre, Southampton, UK"
      ],
      "name": "P Howarth"
    },
    {
      "affiliations": [
        "School of Clinical and Experimental Sciences, University of Southampton, NIHR Southampton Biomedical Research Centre, Southampton, UK"
      ],
      "name": "J Arron"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson- Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK"
      ],
      "name": "L Heaney"
    },
    {
      "affiliations": [
        "Genentech, Inc., San Francisco, USA"
      ],
      "name": "D Choy"
    },
    {
      "affiliations": [
        "NIHR Oxford Respiratory BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "E Marchi"
    },
    {
      "affiliations": [
        "NIHR Oxford Respiratory BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "T Hinks"
    },
    {
      "affiliations": [
        "Department of Respiratory Sciences, University of Leicester, Leicester Respiratory NIHR BRC, Glenfield Hospital, Leicester, UK"
      ],
      "name": "P Bradding"
    }
  ],
  "title": "S105 The airway transcriptome in type2 cytokine biomarker-high and -low severe asthma",
  "uid": "dd75e32a-057d-5418-afb0-a2ea42b56c86"
}