Dataset Information

Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis.

ABSTRACT: BACKGROUND:Although eosinophilic oesophagitis (EoE) is putatively mediated by an abnormal response to food antigen, the oesophagus is considered relatively impermeable to large molecules. AIM:To assess whether food antigens penetrate the oesophageal mucosa in patients with EoE. METHODS:Anti-gliadin staining was performed in three groups: active EoE, inactive EoE and EoE patients on a low or gluten free diet. To appraise the specificity of our results, we also performed gliadin staining on six patients without oesophageal disease who were consuming gluten. The groups with EoE on gluten also underwent endoscopic infusion with gluten containing soy sauce and repeat biopsies during the endoscopy. We measured eosinophil density, dilated intercellular spaces (on a 0-4+ scale) and gliadin in oesophageal mucosa by immunofluorescence. RESULTS:Patients with active EoE had significantly greater epithelial density of anti-gliadin staining when compared to inactive EoE (P < 0.0065) and gluten-free patients (P < 0.0008) at baseline and after soy infusion. Gliadin was not detected in non-EoE control patients. The distribution of gliadin was both cytoplasmic and nuclear. There was good correlation of dilated intercellular spaces grade and total gliadin staining intensity (r = 0.577, P = 0.0077). Acute oesophageal perfusion of a commercial gliadin-rich soy sauce did not lead to an increase in gliadin staining in active or inactive EoE. CONCLUSION:These findings suggest, although do not prove, that antigen penetration in active eosinophilic oesophagitis might be facilitated by impairment of epithelial integrity.

SUBMITTER: Marietta EV

PROVIDER: S-EPMC6944330 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis.

Marietta E V EV Geno D M DM Smyrk T C TC Becker A A Alexander J A JA Camilleri M M Murray J A JA Katzka D A DA

Alimentary pharmacology & therapeutics 20161122 3

<h4>Background</h4>Although eosinophilic oesophagitis (EoE) is putatively mediated by an abnormal response to food antigen, the oesophagus is considered relatively impermeable to large molecules.<h4>Aim</h4>To assess whether food antigens penetrate the oesophageal mucosa in patients with EoE.<h4>Methods</h4>Anti-gliadin staining was performed in three groups: active EoE, inactive EoE and EoE patients on a low or gluten free diet. To appraise the specificity of our results, we also performed glia ...[more]

PMID: 27878833

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Project description:ObjectiveThere are no disease-modifying therapies for the treatment of eosinophilic oesophagitis (EoE), which is driven by non-IgE-mediated allergic inflammation. A recent clinical trial of milk epicutaneous immunotherapy (EPIT) has shown initial promise, with 47% of treated EoE patients tolerating milk without recurrence of disease. Mechanisms of EPIT in EoE have not been studied in humans. Here, we identify transcriptional changes in the peripheral CD4+ T-cell compartment during active EoE and following EPIT.MethodsRNA isolation, sequencing and integrative data analysis were performed on peripheral CD4+ T cells isolated from 15 of 20 patients enrolled in a clinical trial of EPIT for EoE. Gene expression changes in peripheral CD4+ T cells were examined during diet therapy and following trial of milk antigen EPIT.ResultsWe identify 244 differentially expressed genes in peripheral blood CD4+ cells of EoE patients consuming versus those eliminating milk, and 129 DEGs in CD4+ cells were isolated after EPIT versus after placebo (FDR ≤ 0.05). Gene set enrichment analysis identifies enrichment of hallmark interferon-α and interferon-γ response pathways in peripheral CD4+ T cells from EoE patients during active disease on a milk-containing diet. We demonstrate overlap of this gene signature with the altered gene expression signature seen in EoE patient biopsy tissue. EPIT therapy response is associated with significant enrichment in pathways related to T-cell receptor signalling (P = 1.16 × 10-14), antigen presentation and costimulation, and cytokine signalling (P = 1.11 × 10-16), as well as upregulation of genes associated with regulatory T-cell function.ConclusionsEoE is associated with distinct global transcriptional changes in CD4+ T cells, one feature of which is an IFN response signature. Clinically favorable response to EPIT is likely multifactorial but is associated with a distinct transcriptional profile in peripheral CD4+ cells supporting the hypothesis that EPIT alters peripheral CD4+ responses in EoE patients.

Project description:ObjectiveThe influence of eosinophilic oesophagitis (EoE)-associated inflammation upon oesophageal epithelial biology remains poorly understood. We investigated the functional role of autophagy in oesophageal epithelial cells (keratinocytes) exposed to the inflammatory EoE milieu.DesignFunctional consequences of genetic or pharmacological autophagy inhibition were assessed in endoscopic oesophageal biopsies, human oesophageal keratinocytes, single cell-derived ex vivo murine oesophageal organoids as well as a murine model recapitulating EoE-like inflammation and basal cell hyperplasia. Gene expression, morphological and functional characterisation of autophagy and oxidative stress were performed by transmission electron microscopy, immunostaining, immunoblotting, live cell imaging and flow cytometry.ResultsEoE-relevant inflammatory conditions promoted autophagy and basal cell hyperplasia in three independent murine EoE models and oesophageal organoids. Inhibition of autophagic flux via chloroquine treatment augmented basal cell hyperplasia in these model systems. Oesophageal keratinocytes stimulated with EoE-relevant cytokines, including tumour necrosis factor-α and interleukin-13 exhibited activation of autophagic flux in a reactive oxygen species-dependent manner. Autophagy inhibition via chloroquine treatment or depletion of Beclin-1 or ATG-7, augmented oxidative stress induced by EoE-relevant stimuli in murine EoE, oesophageal organoids and human oesophageal keratinocytes. Oesophageal epithelia of paediatric EoE patients with active inflammation displayed increased autophagic vesicle content compared with normal and EoE remission subjects. Functional flow cytometric analysis revealed autophagic flux in human oesophageal biopsies.ConclusionsOur findings reveal for the first time that autophagy may function as a cytoprotective mechanism to maintain epithelial redox balance and homeostasis under EoE inflammation-associated stress, providing mechanistic insights into the role of autophagy in EoE pathogenesis.

Dataset Information

Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis.

Publications

Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis.

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