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Inflammatory Epithelial and Macrophage Pathways Underlie Residual Asthma Exacerbations in Urban Children Treated with Mepolizumab

ABSTRACT: While biologic therapies targeting type 2 (T2) inflammation reduce acute exacerbation rates in children with asthma and T2 inflammation, exacerbations still occur, and the underlying molecular mechanisms are poorly defined. We aimed to identify multiple distinct molecular mechanisms implicated in asthma exacerbations by characterizing respiratory illnesses among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab versus placebo

ORGANISM(S): Homo sapiens

PROVIDER: GSE292059 | GEO | 2025/08/07

REPOSITORIES: GEO

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			Action	DRS
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	GSE292059_counts_raw.tsv.gz	Tabular
	GSE292059_hgnc_ensembl_id_mapping.tsv.gz	Tabular
	GSE292059_modules_normalized_expr.tsv.gz	Tabular
	GSE292059_voom_normalized_gene_expr.tsv.gz	Tabular

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Mechanisms Underlying Asthma Exacerbations Prevented and Persistent with Immune Based Therapy: A Systems Approach Phase 2 (MUPPITS-2)

Project description:A Trial of Mepolizumab Adjunctive Therapy for the Prevention of Asthma Exacerbations in Urban Children (MUPPITS-2). ClinicalTrials.gov Identifier: NCT03292588

2022-08-13 | GSE192861 | GEO

Endotype of Allergic Asthma with Airway Obstruction in Urban Children

Project description:In the first decade of life, high-asthma risk urban children develop stable phenotypes of respiratory health versus disease that link early life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of nasal gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and non-allergic asthma.

2021-04-01 | GSE145505 | GEO

LPS binding protein and activation signatures are upregulated during asthma exacerbations in children

Project description:Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS.

2023-09-12 | GSE96530 | GEO

NHLBI TOPMed: TReating Children to Prevent EXacerbations of Asthma (TREXA)

Project description:NHLBI TOPMed: TReating Children to Prevent EXacerbations of Asthma (TREXA)

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NHLBI TOPMed: TReating Children to Prevent EXacerbations of Asthma (TREXA)

Project description:NHLBI TOPMed: TReating Children to Prevent EXacerbations of Asthma (TREXA)

| PRJNA498743 | ENA

Expression in induced sputum during acute exacerbations in asthmatic children with/without chronic airflow obstruction

Project description:Asthma exacerbations are associated with subsequent deficits in lung function. Here, we tested the hypothesis that a specific pattern of inflammatory responses during acute exacerbations may be associated with susceptibility to chronic airway obstruction.

2010-03-29 | GSE19903 | GEO

Peripheral blood mononuclear cells HELP-tagging cytosine methylation data (Albert Einstein College of Medicine)

Project description:Obesity-associated asthma is recognized as a distinct entity with non-atopic T-helper 1 polarized systemic inflammation. DNA methylation is linked with T helper cell maturation and is associated with inflammatory patterns in asthma and obesity. However, it is unknown whether pathologic dysregulation of DNA methylation patterns occurs in obesity-associated asthma. Using HELP-tagging, we studied epigenome wide DNA methylation in peripheral blood mononuclear cells in 8 urban minority obese asthmatic pre-adolescent children and compared it to methylation in groups of 8 children with asthma alone, obesity alone and healthy controls. Ingenuity Pathway Analysis was used to identify biological pathways that were differentially targeted by methylation dysregulation. We found that obese asthmatics had distinct epigenome wide methylation patterns associated with decreased promoter methylation of a subset of genes, including RANTES, IL-12R and TBX21 and increased promoter methylation of CD23, a low affinity receptor for IgE and of TGFM-NM-2, inhibitor of Th cell activation. T cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These methylation patterns suggest that methylation is associated with non-atopic inflammation observed in obese asthmatic children compared to children with asthma alone and obesity alone. Our findings suggest a role of DNA methylation in the observed inflammatory patterns in pediatric obesity-associated asthma in minorities. 32 HpaII test

2014-04-14 | E-GEOD-43705 | biostudies-arrayexpress

High-Dimensional Analysis of Type 2 Lymphocyte Dynamics During Mepolizumab Treatment in Severe Asthma

Project description:Background Although the type 2 biologics mepolizumab and dupilumab show clinical efficacy in severe asthma, their influence on circulating lymphocytes is largely unknown. Here, we studied their impact on type 2 lymphocytes in severe asthma. Methods We performed high-parameter flow cytometry analysis of peripheral blood mononuclear cells from 40 patients with severe asthma before, and after 4 and 12 months of mepolizumab (n = 33) or dupilumab (n = 7) treatment, focusing on type 2 lymphocytes. Additionally, we performed single-cell RNA sequencing (scRNA-seq) (n = 3) and stimulation experiments of type 2 lymphocytes (n = 3) to explore transcriptional and functional changes associated with mepolizumab treatment. Results Mepolizumab treatment increased circulating type 2 innate lymphoid cell (ILC2), type 2 T helper (Th2) and type 2 cytotoxic (Tc2) cell frequencies, skewing ILC2 towards a CD117low signature with high CD62L expression, and Th2/Tc2 cells towards a CD45RA−CD62L+ central memory phenotype. Dupilumab-treated patients also showed increased frequencies of total ILC2 and CD117low ILC2. Mepolizumab treatment reduced the expression of tissue homing receptors CXCR4 in ILC2, and GPR183 in ILC2, Th2, and Tc2 cells while enhancing their type 2 cytokine producing capability in response to alarmins. Conclusion Mepolizumab increases the frequencies of circulating ILC2, Th2, and Tc2 cells, with reduced tissue homing receptor expression but increased type 2 cytokine production potential. This reveals a potentially new mechanism for how mepolizumab reduces airway inflammation by re-directing trafficking of inflammatory type 2 lymphocytes away from airway-homing, with implications for the possibility of achieving biologics-free remission in asthma.

2025-08-06 | GSE304665 | GEO

Transcriptome networks identify susceptibility to frequent asthma exacerbations

Project description:Transcriptome networks identify susceptibility to frequent asthma exacerbations

| PRJNA869110 | ENA

German cockroach subcutaneous immunotherapy: Impact on nasal responses and allergen-specific immunity among urban children with asthma

Project description:Background: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children.Objective: To determine if nasal allergen challenge (NAC) responses to cockroach allergen would improve following one year of SCIT.Methods: Urban children with asthma, cockroach-sensitized (skin prick test [SPT] and serum specific IgE) and reactive on NAC, participated in a yearlong randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean total nasal symptoms scores (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, SPT wheal size, serum allergen-specific antibody production and T-cell responses to cockroach allergen were assessed.Results: Changes in mean NAC TNSS did not differ between SCIT-assigned (n=28) versus placebo-assigned (n=29) participants (p=0.63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach sIgE decreased to a similar extent in both groups, while decreased cockroach SPT wheal size was greater among SCIT participants (p=0.04). A 200-fold increase in cockroach sIgG4 was observed among subjects receiving SCIT (p<0.001) but was unchanged in the placebo group. T-cell interleukin-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (p=0.002), while no effect was observed for interleukin-10 or interferon-gamma.Conclusion: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum sIgG4 production and down-modulation of allergen stimulated T-cell responses.

2024-12-18 | GSE250580 | GEO

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