Blood-based Molecular Endotyping of Fibrotic Hypersensitivity Pneumonitis Identifies Two Immune Subtypes with Divergent Clinical Outcomes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE318816 | GEO | 2026/06/12
REPOSITORIES: GEO
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Project description:We analysed data collected as part of the Biomarkers of Acute Serious Illness in Children (BASIC) study. BASIC was a prospective cohort study that enrolled critically ill children admitted to four PICUs in London and Eastern England, UK, during emergency transport by the Children’s Acute Transport Service (CATS), the regional paediatric critical care retrieval service from 2014–2016. We aimed to identify, and validate, shared features of immune dysfunction (\"endotypes\") and assess association with clinically important outcomes (primary outcome: ventilator-free days at day 30). Whole blood was sampled into RNA-stabilising tubes (PAXgene, Qiagen, Germany) from recruited patients immediately during paediatric critical care retrieval. Samples were initially stored on ice packs (4ºC) prior to arrival to the admitting PICU, before storage at -80ºC and processing in batches using Illumina Human-HT-12 version 4 Expression BeadChips (Illumina, CA, USA). Statistical analysis was undertaken in R: A Language and Environment for Statistical Computing (version 4.4.1). Microarray data were compiled, log2 transformed and normalised. Of 384 samples assay, 382 met quality control criteria and went forwards for bioinformatics analysis. We used the top 15% (~5000) most variable transcript probes in the dataset before using k-means clustering (Hartigan and Wong algorithm) with two centres to determine BASIC endotype membership for individual children at retrieval to PICU. BASIC endotype membership was internally validated with a train/validation (2/3 training, 1/3 validation) partition of the dataset, and a nested cross-validation implementation of GLMNet. We identified two robust endotypes, BASIC endotype 1 (122, 31.9%, children), and BASIC endotype 2 (260, 68.1%, children), present in children with diverse illnesses and age groups. BASIC endotype 1 membership was associated with 4.1 (95% CI 2.0–6.2) days of increased length of mechanical ventilation and a non-significant association with mortality. BASIC endotype 1 membership was associated with increase naïve and resting memory CD4 T cell proportions, lower neutrophil proportions and lower gene expression sets associated with tumour necrosis factor (TNF)-α, interferon-γ, interferon-α, and interleukin-6/JAK/STAT pathways in comparison with BASIC endotype 2. These BASIC endotypes may enable stratified trials of treatment for immune dysfunction.
2025-09-30 | E-MTAB-15164 | biostudies-arrayexpress
Project description:Rationale: Fibrotic hypersensitivity pneumonitis is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in fibrotic hypersensitivity pneumonitis in single-cell resolution. Methods: Single-cell 5’ RNA sequencing was conducted on peripheral blood mononuclear cells and bronchoalveolar lavage cells obtained from 45 patients with fibrotic hypersensitivity pneumonitis, 63 idiopathic pulmonary fibrosis, 4 non-fibrotic hypersensitivity pneumonitis, and 36 healthy controls in the United States and Mexico. Analyses included differential gene expression (Seurat), transcription factor activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3/Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and controls and 88,336 bronchoalveolar lavage cells from 19 patients were profiled. Compared to controls, fibrotic hypersensitivity pneumonitis has elevated classical monocytes (adjusted-p=2.5e-3) and are enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-p<2.2e-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared to both controls and idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis patient cells are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit transcription factor activities indicative of TGFb and TNFa/NFkB pathways. These results are publicly available at https://ildimmunecellatlas.org. Conclusions: Single-cell transcriptomics of fibrotic hypersensitivity pneumonitis patients uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells – reflecting this disease’s unique inflammatory T-cell driven nature – as well as increased S100Ahi and CCL3hi/CCL4hi classical monocytes also observed in idiopathic pulmonary fibrosis. Both cell populations may guide the development of new biomarkers and therapeutic interventions.
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Project description:Atopic dermatitis (AD) is clinically heterogeneous, but reproducible molecular endotypes remain incompletely defined. By integrating >1,300 lesional and non-lesional skin transcriptomes from 30 studies, we identified two robust AD endotypes that share a conserved lesional core program of barrier disruption and type 2 activation. In contrast to endotype 1 (62%), endotype 2 (38%) was distinguished by a compact 108-gene innate-inflammatory signature (including IL1B and IL6), increased myeloid infiltration, and Staphylococcus aureus-associated dysbiosis. Endotype assignment was stable across longitudinal datasets, with only limited, non-systematic switching upon systemic treatment. Analysis of trial and observational data provided preliminary evidence for lower clinical response and higher residual molecular activity under dupilumab in endotype 2 compared to endotype 1. Interaction modeling of Th2 and innate module activity revealed a Th2-amplified innate state that predicts endotype 2, paralleling functional experiments in which IL-1b/IL-6 synergize with Th2 cytokines to exacerbate keratinocyte inflammation and to impair keratinocyte differentiation. Our findings offer new insights into the biological diversity of AD and establish a robust foundation for mechanistic stratification, with implications for therapeutic strategies.
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2022-07-12 | E-MTAB-7581 | biostudies-arrayexpress
Project description:This study aimed to identify circulating immune cell populations associated with disease severity and progression in fibrotic hypersensitivity pneumonitis (fHP). Using single-cell RNA sequencing of peripheral blood mononuclear cells from 33 fHP patients (NCT02958917) and 36 sex-matched healthy controls (GSE196735, pools 1-3), we identified significant shifts in immune cell composition. Compared to controls, fHP patients exhibited a marked increase in classical monocytes (CD14⁺), non-classical monocytes (CD16⁺), and myeloid-derived dendritic cells. Classical monocytes, in particular, were strongly correlated with baseline lung fibrosis severity—quantified by data-driven texture analysis of high-resolution computed tomography—and with reduced progression-free survival. Pathway analysis revealed that monocytes from patients with severe disease were enriched for inflammatory and metabolic processes, whereas those from patients with poor outcomes showed upregulation of interferon and NF-κB signaling. These findings highlight peripheral monocytes as promising prognostic biomarkers in fHP and suggest their role in driving fibrotic progression through dysregulated immune responses.
2026-04-01 | GSE317902 | GEO
Project description:Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has exhibited significant efficacy in the treatment of EGFR-mutated non-small cell lung cancer. Drug-induced interstitial lung disease is a potentially fatal complication of osimertinib therapy. Although there is often an elevated number of lymphocytes in the bronchoalveolar lavage fluid (BALF) in patients with drug-induced pneumonitis, the precise involvement of lymphocytes in osimertinib-induced pneumonitis remains unclear. Therefore, we investigated the pathogenesis of osimertinib-induced pneumonitis using BALF obtained from patients with osimertinib-induced pneumonitis and a mouse model of osimertinib-induced pneumonitis. Methods: Mass cytometry was used to analyze BALF cells obtained from patients with osimertinib-induced pneumonitis. A mouse model of osimertinib-induced pneumonitis was established by the administration of naphthalene and osimertinib. Histopathological evaluation, body weight measurements, BALF analysis, and RNA sequencing were performed to investigate immune cell involvement and the mechanisms underlying osimertinib-induced pneumonitis. Results: Analysis of BALF cells obtained from patients with osimertinib-induced pneumonitis revealed the expansion of CCR7+ CD45RA+ naïve T cells. In the mouse model, osimertinib administration following naphthalene-induced club cell injury exacerbated lung inflammation, leading to increased inflammatory cell infiltration and body weight loss. BALF analysis revealed elevated proportions of T cells, including CD4+ and double-negative T cells, in mice administered osimertinib after naphthalene treatment. Bulk RNA sequencing identified upregulation of chemokine-related biological processes, with increased the expression of C-C motif chemokine ligand 21 (Ccl21) and C-C motif chemokine ligand 8 (Ccl8) in lung tissue, and immunostaining confirmed elevated expression of Ccl21 and Ccl8 in the distal bronchiolar epithelium. Conclusion: This study provides insights into the immune mechanisms underlying osimertinib-induced pneumonitis, which are crucial for overcoming this fatal complication in EGFR-positive non-small cell lung cancer.
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Project description:Childhood asthma is a complex disease historically defined by partially overlapping clinical features, including recurrent respiratory symptoms and reversible airway obstruction. However, the heterogeneity observed in clinical disease and airway pathology suggests that the “traditionally” defined asthma population is composed of multiple subgroups (i.e., endotypes), each with a distinct pathogenesis. Gene expression profiling of bronchial airway brushings identified the type 2-high asthma endotype, defined by excessive airway inflammation driven by type 2 cytokines, which was found in ~50% of subjects. Importantly, response to inhaled corticosteroid treatment was limited to this type 2-high endotype. The clinical utility of type 2-high asthma endotyping and the discovery of other endotypes have been limited by the need to perform an invasive bronchoscopy to obtain the bronchial brushings for analysis. Moreover, research bronchoscopies cannot be performed in children. Less invasive methods for the identification of asthma endotypes are needed. To this end, we found that the type 2-high asthma endotype can be identified by gene expression profiling of minimally invasive nasal airway epithelium brushings. Moreover, we found high nasal expression of the type 2 cytokine, IL-13,4 was associated with higher risk of asthma exacerbations among Puerto Ricans, who have the highest asthma morbidity and mortality in the U.S. Herein, we propose to use whole transcriptome sequencing of nasal airway epithelial brushings from Puerto Rican children with asthma to identify the type 2-high and other asthma endotypes, which relate to severity and drug response.
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Project description:Background: Few studies have analyzed the blood transcriptome in atopic dermatitis (AD). Objective: We explored blood transcriptomic features of moderate to severe AD. Results: AD patients showed pronounced inflammatory expression signatures with increased myeloid and IL-5-related patterns, and clearly segregated into 2 distinct clusters, with striking differences in particular for transcripts involved in eosinophil signaling. The eosinophil-high endotype showed a more pronounced global dysregulation, a positive correlation between disease activity and signatures related to IL-5 signaling, and strong correlations with several target proteins of antibodies or small molecules under development for AD. In contrast, the eosinophil-low endotype showed little transcriptomic dysregulation and no association between disease activity and gene expression. Clinical improvement with receipt of dupilumab was accompanied by a decrease of innate immune responses and an increase of lymphocyte signatures including B-cell activation and natural killer cell composition and/or function. The proportion of super responders was higher in the eosinophil-low endotype (32% vs 11%). Continued downregulation of IL18RAP, IFNG, and granzyme A in the eosinophil-high endotype suggests a residual disturbance of natural killer cell function despite clinical improvement. Conclusion: AD can be stratified into eosinophilic and noneosinophilic endotypes; such stratification may be useful when assessing stratified trial designs and treatment strategies.
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