Project description:Therapies targeting interleukin-5 (IL-5) or its receptor (IL-5Rα) are used to treat patients with severe eosinophilic asthma. The therapeutic effect are considered being the suppression of eosinophil activation and elimination. However, the impact of these therapies on mast cells (MCs) and their progenitors has remained largely unexplored. We investigate whether targeting the IL-5 pathway in severe asthma patients could reduce blood MC progenitors
Project description:Aberrant immune response is a hallmark of asthma, with 5-10% of patients suffering from severe disease exhibiting poor response to standard treatment. A better understanding of the immune responses contributing to disease heterogeneity is critical for improving asthma management. Here we show a significant association of airway CD8+ effector memory T cells re-expressing CD45RA (TEMRAs), but not CD8+ CD45RO+ or tissue resident memory (TRM) T cells, with asthma duration in patients with severe asthma (SA) but not mild to moderate asthma (MMA). Higher frequencies of IFN-g+ CD8+ TEMRAs compared to IFN-g+ CD45RO+ T cells were detected in SA airways, and the TEMRAs from SA but not MMA patients proliferated ex vivo, although both expressed cellular senescence-associated biomarkers. Prompted by the transcriptomic profile of SA CD8+ TEMRAs and proliferative response to IL-15, airway IL15 expression measured higher in SA compared to MMA patients. Our findings add a new dimension to understanding asthma heterogeneity identifying IL-15 as a potential target for treatment.
Project description:The IL-13 is a central mediator of allergic asthma. This project investigates the mechanisms by which IL-13 elicits the symptoms of asthma. Keywords: other
Project description:Background: Asthma is highly heterogeneous and severity evaluation is key to asthma management. DNA methylation (DNAm) contributes to asthma pathogenesis. This study aimed to identify nasal epithelial DNAm differences between severe and non-severe asthmatic children and evaluate the impact of environmental exposures. Methods: Thirty-three non-severe and 22 severe asthmatic African-American children were included in an epigenome-wide association study. Genome-wide nasal epithelial DNAm and gene expression were measured. CpG sites associated with asthma severity and environmental exposures and predictive of severe asthma were identified. DNAm was correlated with gene expression. Enrichment for transcription factor (TF) binding sites or histone modifications surrounding DNAm differences were determined. Results: We identified 816 differentially methylated CpG positions (DMPs) and 10 differentially methylated regions (DMRs) associated with asthma severity. Three DMPs exhibited discriminatory ability for severe asthma. Intriguingly, six DMPs were simultaneously associated with asthma, allergic asthma, total IgE, environmental IgE, and FeNO in an independent cohort of children. 27 DMPs were associated with traffic-related air pollution or secondhand smoke. DNAm at 22 DMPs were altered by diesel particles or allergen in human bronchial epithelial cells. DNAm levels at 39 DMPs were correlated with mRNA expression. Proximal to 816 DMPs, three histone marks and several TFs involved in asthma pathogenesis were enriched. Conclusions: Significant differences in nasal epithelial DNAm were observed between non-severe and severe asthma in African-American children, a subset of which may be useful to predict disease severity. These CpG sites are subject to the influences of environmental exposures and may regulate gene expression.
Project description:Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)-4, IL-5 and IL-13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL-5R and IL-5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late-onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non-response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL-5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non-response.
Project description:Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study.
Project description:Gene expression profiles were generated from induced sputum samples in asthma and healthy controls. The study identified differential gene expression and pathways in severe asthma.
Project description:Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and b-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. Unfortunately, no drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. Here we show that N-cadherin, a plasma membrane associated cell-cell adhesion protein upregulated in ASM cells derived from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Pharmacological inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation. ADH-1 prevented bronchoconstriction and actively promoted bronchodilation of airways ex vivo. In human ASM cells, ADH-1 inhibited agonist-induced contraction by disrupting N-cadherin-d-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.