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The gliadin-CFTR connection: new perspectives for the treatment of celiac disease

Familial loss-of-function mutations of the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) channel protein cause cystic fibrosis (CF), the most frequent inherited life-threatening disease in the Caucasian population. A recent study indicates that the gluten/gliadin-der...

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Autores principales: Maiuri, Luigi, Villella, Valeria R., Raia, Valeria, Kroemer, Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429699/
https://www.ncbi.nlm.nih.gov/pubmed/30898172
http://dx.doi.org/10.1186/s13052-019-0627-9
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author Maiuri, Luigi
Villella, Valeria R.
Raia, Valeria
Kroemer, Guido
author_facet Maiuri, Luigi
Villella, Valeria R.
Raia, Valeria
Kroemer, Guido
author_sort Maiuri, Luigi
collection PubMed
description Familial loss-of-function mutations of the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) channel protein cause cystic fibrosis (CF), the most frequent inherited life-threatening disease in the Caucasian population. A recent study indicates that the gluten/gliadin-derived peptide (P31–43) can cause CFTR inhibition in intestinal epithelial cells, thus causing a local stress response that contributes to the immunopathology of celiac disease (CD). Accordingly, an increased prevalence of CD has been observed in several cohorts of CF patients. CD is characterized by a permanent intolerance to gluten/gliadin proteins occurring in a proportion of susceptible individuals who bear the human leukocyte antigen (HLA) DQ2/DQ8. In CD, perturbations of the intestinal environment, together with the activation of the innate immune system by P31–43, are essential for rendering other immunodominant gliadin peptide fully antigenic, thus triggering an adaptive immune response with an autoimmune component. P31–43-induced CFTR inhibition elicits the danger signals that ignite the epithelial stress response and perturb epithelial proteostasis. Importantly, potentiators of CFTR channel gating, such as the FDA-approved drug Ivacaftor, prevent P31–43 driven CFTR inhibition and suppress the gliadin-induced stress response in cells from celiac patients, as well as the immunopathology developing in gliadin-sensitive mice. Thus, CFTR potentiators may represent a novel therapeutic option for celiac patients.
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spelling pubmed-64296992019-04-04 The gliadin-CFTR connection: new perspectives for the treatment of celiac disease Maiuri, Luigi Villella, Valeria R. Raia, Valeria Kroemer, Guido Ital J Pediatr Commentary Familial loss-of-function mutations of the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) channel protein cause cystic fibrosis (CF), the most frequent inherited life-threatening disease in the Caucasian population. A recent study indicates that the gluten/gliadin-derived peptide (P31–43) can cause CFTR inhibition in intestinal epithelial cells, thus causing a local stress response that contributes to the immunopathology of celiac disease (CD). Accordingly, an increased prevalence of CD has been observed in several cohorts of CF patients. CD is characterized by a permanent intolerance to gluten/gliadin proteins occurring in a proportion of susceptible individuals who bear the human leukocyte antigen (HLA) DQ2/DQ8. In CD, perturbations of the intestinal environment, together with the activation of the innate immune system by P31–43, are essential for rendering other immunodominant gliadin peptide fully antigenic, thus triggering an adaptive immune response with an autoimmune component. P31–43-induced CFTR inhibition elicits the danger signals that ignite the epithelial stress response and perturb epithelial proteostasis. Importantly, potentiators of CFTR channel gating, such as the FDA-approved drug Ivacaftor, prevent P31–43 driven CFTR inhibition and suppress the gliadin-induced stress response in cells from celiac patients, as well as the immunopathology developing in gliadin-sensitive mice. Thus, CFTR potentiators may represent a novel therapeutic option for celiac patients. BioMed Central 2019-03-21 /pmc/articles/PMC6429699/ /pubmed/30898172 http://dx.doi.org/10.1186/s13052-019-0627-9 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Commentary
Maiuri, Luigi
Villella, Valeria R.
Raia, Valeria
Kroemer, Guido
The gliadin-CFTR connection: new perspectives for the treatment of celiac disease
title The gliadin-CFTR connection: new perspectives for the treatment of celiac disease
title_full The gliadin-CFTR connection: new perspectives for the treatment of celiac disease
title_fullStr The gliadin-CFTR connection: new perspectives for the treatment of celiac disease
title_full_unstemmed The gliadin-CFTR connection: new perspectives for the treatment of celiac disease
title_short The gliadin-CFTR connection: new perspectives for the treatment of celiac disease
title_sort gliadin-cftr connection: new perspectives for the treatment of celiac disease
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429699/
https://www.ncbi.nlm.nih.gov/pubmed/30898172
http://dx.doi.org/10.1186/s13052-019-0627-9
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