ScRNA-seq analysis of the effect IL20RB knock-out in esophageal immune cells of an eosinophilic esophagitis (EoE) mouse model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE190482 | GEO | 2022/05/20
REPOSITORIES: GEO
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Project description:Esophageal biopsy RNA was isolated from proximal esophageal biopsied RNA from patients with EoE-like inflammatory diseases (EoE-like esophagitis, lymphocytic esophagitis, non-specific esophagitis), patients with active EoE, patients with GERD, and unaffected healthy controls. EoE-like inflammatory disease patients were clinically active at the time when biopsies were taken. None of the patients (EoE-like inflammatory diseases, EoE, GERD and controls) were under anti-eosinophil treatment (including dietary restrictions). The quality of the RNA-seq data was assessed using fastqc v. 0.11.5 1) and RSeQC v. 2.6.4 2). The reads were mapped to the reference genome using HiSat2 v. 2.1.0 3). FeatureCounts v. 1.6.0 4) was used to count the number of reads overlapping with each gene as specified in the genome annotation (Homo_sapiens.GRCh38.94). The Bioconducture package DESeq2 5) was used to test for differential gene expression between the experimental groups. TopGo 6) was used to identify gene ontology terms containing unusually many differentially expressed genes. An interactive Shiny application was set up to facilitate the exploration and visualisation of the RNA-seq results. All analyses were run in R version 3.4.4 (2018-03-15)
2022-02-28 | GSE148381 | GEO
Project description:RNA sequencing analysis of proximal and distal esophageal biopsies from a small cohort of EoE, GERD, and control patients was performed to identify differentially expressed genes.
2018-12-31 | GSE41687 | GEO
Project description:Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue in pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA-sequencing of paired esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease (GERD). Unbiased analysis of differentially expressed genes in tissue revealed a strong interferon signature that was significantly enriched in EoE patients as compared to patients with GERD. Both type I and type II interferon responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of interferon gene sets was observed in pediatric EoE biopsies as compared to non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that peripheral CD4+ T cells from children with EoE produce IFNG upon activation with EoE-causal allergens. Together, this work identifies a conserved interferon signature in pediatric and adult EoE, highlighting a role for non-type 2 inflammatory networks in the disease process.
2020-08-22 | GSE156651 | GEO
Project description:Background: Massive eosinophil infiltration into the esophagus causes subepithelial fibrosis and esophageal stricture in patients with eosinophilic esophagitis (EoE). However, the pathogenesis of esophageal fibrosis remains unclear. Objective: The present study aimed to elucidate the cellular and molecular mechanisms underlying the induction of esophageal fibrosis. Methods: We established a murine model of EoE accompanied by fibrotic responses following long-term intranasal administration of house dust mite (HDM) antigen. Using this murine model, we investigated the characteristics of immune cells infiltrating the fibrotic region of the inflamed esophagus using flow cytometry and histological analyses. We also analyzed the local inflammatory sites in the esophagus of patients with EoE using single-cell RNA sequencing, flow cytometry, and immunohistochemistry.
2024-08-05 | GSE249276 | GEO
Project description:Analysis of steady-state mRNA levels in 27 samples from healthy controls and patients with fibrostenotic EoE and non-fibrostenotic EoE. Participants range 5 – 18 years old. EoE participants had >15 eosinophils per hpf (eos/hpf) and were classified as fibrostenotic (FS) or non-fibrostenotic (non-fs). FS EoE: having either a) a stricture and/or b) grade 2 or 3 concentric esophageal rings and an esophageal distensibility < 15 mm. Non-fs EoE: no clinical evidence for stricture, circumferential rings or history of food impaction. Included control subjects had no identified abnormalities on endoscopy or histology. Results provide insight into the pathways involved in fibrostenotic remodeling in EoE.
2023-04-08 | GSE197702 | GEO
Project description:This study sought to evaluate the diffferential gene expression of human Eosinophilic Esophagitis (EoE) patients compared to control patients. Abstract from associated publication: Eosinophilic Esophagitis (EoE) is a chronic allergic disease characterized by progressive inflammation of the esophageal mucosa. While the transcriptome of EoE has been reported, few studies have examined the genetics among both adult and pediatric EoE populations. Here, we use microarray analysis to interrogate gene expression using esophageal biopsies from EoE and Control subjects with a wide age distribution. Analysis of differential gene expression and prediction of impaired pathways was compared using conventional transcriptome analysis programs and an artificial intelligence-based ADVAITA program. Principal Components Analysis revealed samples cluster by disease status (EoE and Control) irrespective of clinical features like sex, age, and disease severity. Global transcriptomic analysis revealed differential expression of several genes previously reported in EoE (CCL26, CPA3, POSTN, CTSC, ANO1, CRISP3, SPINK7). In addition, we identified differential expression of several genes from the MUC and SPRR families, which has not been previously reported. Our findings suggest their involvement in impaired barrier integrity and loss of epidermal cell differentiation in EoE patients. These findings present two new gene families that are differentially expressed in EoE patients in both adult and pediatric populations, which presents an opportunity for a future therapeutic targets that would be useful in a large demographic of patients.
2023-08-10 | GSE228083 | GEO
Project description:Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the recruitment of eosinophils to the esophagus, resulting in chronic inflammation. We sought to understand the cellular populations present in the esophageal biopsies of patients with EoE and to determine how these populations are altered between active disease and remission. To this end, we analyzed cells from the esophageal biopsies, duodenal biopsies, and peripheral blood of EoE patients in active disease or remission using single-cell RNA and TCR sequencing. We identified gene modules regulated by transcription factors from the NF-κB family that characterize activated eosinophils in patients with active disease. Pathogenic effector Th2 (peTh2) cells present in the esophageal biopsies of patients with active disease expressed unique gene signatures associated with the synthesis of eicosanoids that are predicted to directly promote activation of tissue-resident eosinophils. The tissue-resident peTh2 population also exhibited clonal expansion, suggesting antigen-specific activation. Peripheral CRTH2+CD161- and CRTH2+CD161+ memory CD4+ T cells were enriched for either a conventional Th2 phenotype or a peTh2 phenotype, respectively. These cells also exhibited significant clonal expansion and convergence of TCR sequences, indicating that these cells are expanded in response to a defined set of antigens. The esophagus-homing receptor GPR15 was upregulated by peripheral peTh2 clonotypes that were also detected in the esophagus. Lastly, peTh2 cells and GPR15+ cells were enriched among milk-reactive CD4+ T cells in patients with milk-triggered disease, suggesting that peTh2 cells in EoE are an expanded, food antigen-specific population with enhanced esophagus homing potential.
2021-08-13 | GSE175930 | GEO
Project description:Introduction Disruption of the epithelial barrier can induce eosinophilic esophagitis (EoE), a TH2-mediated food- and aeroallergen associated chronic inflammatory disease 1, 2. The expression of IL-20 subfamily cytokines, IL-19, IL-20 and IL-24, is increased in TH2-mediated diseases, yet their function in EoE is unknown. Methods Combining RNA-sequencing (RNA-seq) and proteome analysis, we have examined the effects of the IL-20 subfamily on esophageal epithelial cells using patient-derived organoids and an experimental EoE mouse model. Results When stimulated with IL-20 subfamily cytokines patient-derived esophageal organoids showed decreased expression of Filaggrin (FLG) and Filaggrin 2 (FLG2) responsible for epithelial cornification. In agreement, EoE patients with active inflammation showed elevated IL-20 subfamily cytokines and decreased FLG and FLG2 expression. Topical corticosteroid treatment in EoE patients restored filaggrin expression, while reducing IL-20 subfamily cytokines. Abolishment of IL-20 subfamily signalling in Il20R2-/- animals attenuated experimental EoE in an OVA-induced mouse model. In the esophageal keratinocyte cell line, KYSE-180, we identified IL-20 subfamily-induced STAT3 and MAPK (ERK1/2) pathway activation. However, Stat3fl/flKrt5cre mice with an epithelium specific deletion of Stat3 developed exacerbated experimental EoE with a pronounced decrease of Flg2. In line, combined stimulation of patient-derived esophageal organoids with IL-20 subfamily cytokines and pharmacological inhibition of STAT3 resulted in aggravated decrease of FLG and FLG2. In addition, pharmacological STAT3 inhibition resulted in reduced transepithelial electrical resistance (TEER) and increased macromolecular flux in patient-derived air liquid interface (ALI) cultures. Whereas, inhibition of the MAPK (ERK1/2) pathway hampered IL-20 subfamily induced TEER reduction and paracellular flux increment. Finally, MAPK (ERK1/2) inhibitor treatment reduced infiltrating CD45+ immune cells in the esophagus and alleviated experimental EoE in mice. Conclusion We discovered a novel regulatory function of the IL-20 subfamily for epithelial barrier integrity. Aberrant IL-20 subfamily signaling disturbs the epithelial barrier function, while abrogation of IL-20 subfamily and ERK1/2 signaling restores epithelial integrity and attenuates experimental EoE. Therefore, we propose that targeting the IL-20 subfamily pathway could present a novel therapeutic strategy for EoE treatment.
2023-05-10 | PXD031509 | Pride
Project description:Immunotherapy strategies have been studied for IgE-mediated food allergies but have not been studied for non-IgE mediated food allergy disorders, including eosinophilic esophagitis. We interrogated the transcriptional signatures of peripheral CD4+ cells isolated from pediatric eosinophilic esophagitis patients enrolled in a phase IIa clinical trial of milk-antigen epicutaneous immunotherapy. We analyzed differential expression in peripheral CD4+ cells before therapy in patients before and after milk-exclusion diet. RNA-sequencing analysis revealed that there were 244 differentially expressed genes in peripheral blood CD4+ cells of EoE patients consuming milk versus those eliminating it, and 129 DEGs in CD4+ cells isolated after EPIT versus after placebo (FDR<0.05). Gene set enrichment analysis identifies enrichment of hallmark interferon-a and -g response signatures in peripheral CD4+ T cells from EoE patients during active disease on a milk-containing diet. In post-EPIT therapy samples, our analysis identifies enrichment in T-cell receptor signaling, antigen presentation, costimulation, and cytokine signaling pathways. These data suggest a unique peripheral CD4+ T cell gene signature is present in EoE patients during active disease. We observe a distinct transcriptional profile post-EPIT therapy in EoE patients, suggesting that EPIT alters CD4+ responses in EoE patients.
2021-08-03 | GSE173895 | GEO
Project description:To uncover molecular drivers of Eosinophilic Esophagitis (EoE), a global proteome screen of the esophageal biopsies from individuals with and without EoE was performed.
2023-08-01 | PXD040030 | Pride