Neuro-Immune Interactions in the Gut
Mots clés
Abstrait
La description
Hirschsprung`s disease (HD) is diagnosed shortly after birth and is characterized by the absence of enteric nerves in parts of colon [Amiel et al.]. Following surgical correction many patients develop HD-associated enterocolitis (HAEC), a condition distinguished by intestinal inflammation resulting in abdominal distension, severe diarrhea, fever and sepsis [Demehri et al.]. The underlying factors leading to HAEC remain poorly understood and likely involve a defect in epithelial barrier, including decreased mucin production and insufficient immunoglobulin translocation. The establishment of the epithelial barrier is dependent on epithelial recognition of microbial products by innate immune receptors, like toll-like receptors (TLRs) [Peterson et al.]. TLR-dependent epithelial recognition of microflora also coordinates the immune response away from harmless commensal bacteria and towards pathogenic invaders. Both innate and adaptive effector cell functions are influenced by epithelial-derived signals. Under homeostatic conditions commensal bacteria induce anti-inflammatory cytokines in epithelial cells which trigger a tolerogenic phenotype in mucosal antigen presenting cells (APC) resulting in generation of commensal-specific regulatory T cells (Tregs) [Curotto de Lafaille et al.]. During infection, recognition of pathogenic organisms by epithelial cells leads to secretion of inflammatory cytokines thereby inducing an inflammatory APC phenotype which promotes T effector cell (Th1, Th17) generation. The enteric nervous system is directly located underneath the epithelium and controls epithelial cell function. Ablation of enteric glia cells, one of the two cell types of the ENS, in mice is associated with inflammation and enterocolitis [Cornet et al.]. In a study from 2011 Flamant and co-workers demonstrate that enteric glia cells protect from a shigella flexneri invasion by preventing lesions in the epithelial barrier mediated by the glia cell derived neurothrophic factor S-nitrosoglutathione (GSNO) [Flamant et al.]. We hypothesize that the lack of an enteric nervous system in HD patients modulates the microbial recognition of epithelial cells and thereby the phenotype of underlying mucosal APCs and effector T cells; this might be associated with the manifestation of HAEC.
Rendez-vous
Dernière vérification: | 06/30/2018 |
Première soumission: | 07/23/2018 |
Inscription estimée soumise: | 07/30/2018 |
Première publication: | 08/05/2018 |
Dernière mise à jour soumise: | 07/30/2018 |
Dernière mise à jour publiée: | 08/05/2018 |
Date de début réelle de l'étude: | 02/27/2015 |
Date d'achèvement primaire estimée: | 02/27/2020 |
Date estimée d'achèvement de l'étude: | 02/27/2020 |
Condition ou maladie
Phase
Groupes d'armes
Bras | Intervention / traitement |
---|---|
Hirschsprung's disease patients Children diagnosed with Hirschsprung's disease or Hirschsprung's disease associated enterocolitis | |
control patients Children diagnosed and treated for miscellaneous bowel diseases |
Critère d'éligibilité
Sexes éligibles à l'étude | All |
Méthode d'échantillonnage | Non-Probability Sample |
Accepte les bénévoles en santé | Oui |
Critères | Inclusion Criteria: Informed consent Exclusion Criteria: No signed informed consent No blood from patients with weak general state of health |
Résultat
Mesures des résultats primaires
1. Phenotypic analysis of immune and nervous cell populations [5 years]
2. Expression profil [5 years]
3. Histological analysis [5 years]
Mesures des résultats secondaires
1. Microbial metagenomics sequencing [5 years]
2. Identifying genetic defect [5 years]