RÉSUMÉ
Background: Gastro-oesophageal reflux disease (GORD) mechanisms are well described, but the aetiology is uncertain. Coeliac disease (CD), a gluten enteropathy with increased duodenal eosinophils overlaps with GORD. Functional dyspepsia is a condition where duodenal eosinophilia is featured, and a 6-fold increased risk of incident GORD has been observed. Perturbations of the duodenum can alter proximal gastric and oesophageal motor function. We performed a systematic review and meta-analysis assessing the association between CD and GORD. Methods: A systematic search of studies reporting the association of GORD and CD was conducted. CD was defined by combined serological and histological parameters. GORD was defined based on classical symptoms, oesophagitis (endoscopic or histologic) or abnormal 24-h pH monitoring; studies reporting oesophageal motility abnormalities linked with GORD were also included. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random-effects model. Findings: 31 papers were included. Individuals with CD on a gluten containing diet were 3 times more likely to have GORD than controls (OR: 3.37, 95% CI: 2.09-5.44), and over 10 times more likely when compared to those on a gluten free diet (GFD) (OR: 10.20, 95% CI: 6.49-16.04). Endoscopic oesophagitis was significantly associated with CD (OR: 4.96; 95% CI: 2.22-11.06). One year of a GFD in CD and GORD was more efficacious in preventing GORD symptom relapse than treatment with 8 weeks of PPI in non-CD GORD patients (OR: 0.18, 95% CI: 0.08-0.36). Paediatric CD patients were more likely to develop GORD (OR: 3.29, 95% CI: 1.46-7.43), compared to adult CD patients (OR: 2.55, 95% CI: 1.65-3.93). Interpretation: CD is strongly associated with GORD but there was high heterogeneity. More convincingly, a GFD substantially improves GORD symptoms, suggesting a role for duodenal inflammation and dietary antigens in the aetiology of a subset with GORD. Ruling out CD in patients with GORD may be beneficial. Funding: The study was supported by an Investigator Grant from the NHMRC to Dr. Talley.
RÉSUMÉ
INTRODUCTION: An association between functional dyspepsia (FD) and wheat-containing foods has been reported in observational studies; however, an adaptive response has not been demonstrated. We examined whether antigens present in wheat could provoke a response from FD duodenal lymphocytes. METHODS: Lamina propria mononuclear cells (LPMCs) were isolated from duodenal biopsies from 50 patients with FD and 23 controls. LPMCs were exposed to gluten (0.2 mg/mL) or gliadin (0.2 mg/mL) for 24 hours. Flow cytometry was performed to phenotype lymphocytes. Quantitative PCR was used to measure the expression of gliadin-associated T-cell receptor alpha variant ( TRAV ) 26-2. RESULTS: In response to gliadin (but not gluten) stimulation, the effector Th2-like population was increased in FD LPMCs compared with that in controls and unstimulated FD LPMCs. Duodenal gene expression of TRAV26- 2 was decreased in patients with FD compared with that in controls. We identified a positive association between gene expression of this T-cell receptor variant and LPMC effector Th17-like cell populations in patients with FD, but not controls after exposure to gluten, but not gliadin. DISCUSSION: Our findings suggest that gliadin exposure provokes a duodenal effector Th2-like response in patients with FD, supporting the notion that food antigens drive responses in some patients. Furthermore, these findings suggest that altered lymphocyte responses to wheat proteins play a role in FD pathogenesis.
Sujet(s)
Dyspepsie , Humains , Dyspepsie/étiologie , Gliadine/métabolisme , Triticum/génétique , Lymphocytes/métabolisme , Lymphocytes/anatomopathologie , Glutens , Muqueuse intestinale/anatomopathologie , Récepteurs aux antigènes des cellules T/métabolismeRÉSUMÉ
BACKGROUND & AIMS: Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. Based on their cytolytic capacity and surveillance behavior, we investigated whether intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) are actively involved in the shedding of enterocytes into the lumen. METHODS: Intravital microscopy was performed on GFP γδ T cell reporter mice treated with intraperitoneal lipopolysaccharide (10 mg/kg) for 90 minutes to induce tumor necrosis factor-mediated apoptosis. Cell shedding in various knockout or transgenic mice in the presence or absence of blocking antibody was quantified by immunostaining for ZO-1 funnels and cleaved caspase-3 (CC3). Granzyme A and granzyme B release from ex vivo-stimulated γδ IELs was quantified by enzyme-linked immunosorbent assay. Immunostaining for γδ T cell receptor and CC3 was performed on duodenal and ileal biopsies from controls and patients with Crohn's disease. RESULTS: Intravital microscopy of lipopolysaccharide-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, and CD103 knockout or blockade significantly reduced lipopolysaccharide-induced shedding. Furthermore, we found that granzymes A and B, but not perforin, are required for cell shedding. These extracellular granzymes are released by γδ IELs both constitutively and after CD103/E-cadherin ligation. Moreover, we found that the frequency of γδ IEL localization to CC3-positive enterocytes is increased in Crohn's disease biopsies compared with healthy controls. CONCLUSIONS: Our results uncover a previously unrecognized role for γδ IELs in facilitating tumor necrosis factor-mediated shedding of apoptotic enterocytes via CD103-mediated extracellular granzyme release.
Sujet(s)
Antigènes CD/métabolisme , Maladie de Crohn/métabolisme , Entérocytes/physiologie , Granzymes/métabolisme , Intégrines alpha/métabolisme , Lymphocytes intra-épithéliaux/physiologie , Adolescent , Adulte , Animaux , Antigènes CD/génétique , Apoptose , Cadhérines/métabolisme , Caspase-3/métabolisme , Maladie de Crohn/anatomopathologie , Duodénum/anatomopathologie , Entérocytes/métabolisme , Femelle , Techniques de knock-down de gènes , Humains , Iléum/anatomopathologie , Intégrines alpha/génétique , Muqueuse intestinale/immunologie , Muqueuse intestinale/métabolisme , Muqueuse intestinale/anatomopathologie , Lymphocytes intra-épithéliaux/enzymologie , Lymphocytes intra-épithéliaux/anatomopathologie , Microscopie intravitale , Jéjunum/immunologie , Jéjunum/anatomopathologie , Lipopolysaccharides , Mâle , Souris , Souris knockout , Adulte d'âge moyen , Récepteur lymphocytaire T antigène, gamma-delta/métabolisme , Facteur de nécrose tumorale alpha/métabolisme , Jeune adulteRÉSUMÉ
Background: Functional dyspepsia is characterised by chronic symptoms of post-prandial distress or epigastric pain not associated with defined structural pathology. Increased peripheral gut-homing T cells have been previously identified in patients. To date, it is unknown if these T cells were antigen-experienced, or if a specific phenotype was associated with FD. Objective: This study aimed to characterise T cell populations in the blood and duodenal mucosa of FD patients that may be implicated in disease pathophysiology. Methods: We identified duodenal T cell populations from 23 controls and 49 Rome III FD patients by flow cytometry using a surface marker antibody panel. We also analysed T cell populations in peripheral blood from 37 controls and 61 patients. Where available, we examined the number of duodenal eosinophils in patients and controls. Results: There was a shift in the duodenal T helper cell balance in FD patients compared to controls. For example, patients had increased duodenal mucosal Th2 populations in the effector (13.03 ± 16.11, 19.84 ± 15.51, p=0.038), central memory (23.75 ± 18.97, 37.52 ± 17.51, p=0.007) and effector memory (9.80±10.50 vs 20.53±14.15, p=0.001) populations. Th17 populations were also increased in the effector (31.74±24.73 vs 45.57±23.75, p=0.03) and effector memory (11.95±8.42 vs 18.44±15.63, p=0.027) subsets. Peripheral T cell populations were unchanged between FD and control. Conclusion: Our findings identify an association between lymphocyte populations and FD, specifically a Th2 and Th17 signature in the duodenal mucosa. The presence of effector and memory cells suggest that the microinflammation in FD is antigen driven.