Auteur Topic: Medicijn cystic fibrose als behandeling voor coeliakie  (gelezen 593 keer)


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Medicijn cystic fibrose als behandeling voor coeliakie
« Gepost op: december 08, 2018, 16:11:01 »
Volledig artikel in EMBO Journal - na onderstaand nieuwsbericht

Nieuw onderzoek in samenwerkingsverband tussen 19 universiteiten/instituten in Italie, Frankrijk, Duitsland, Zweden en Zwitserland

Celiac disease may be treated with cystic fibrosis drugs
New research investigates the molecular similarities between celiac disease and cystic fibrosis. The results suggest that a compound developed for cystic fibrosis may also treat celiac disease.

Celiac disease is an autoimmune disorder that affects 1 in 141 people in the United States.
The condition is triggered by the consumption of gluten — a protein that can be found in wheat, barley, and rye and in foods such as bread, pasta, and baked goods.
In a person with celiac disease, consuming gluten causes the immune system to attack the mucus that lines the inside of the small intestine.
This can trigger a range of digestive symptoms, such as bloating, nausea, vomiting, chronic diarrhea, and stomach pain.

Current remedies for the disease involve avoiding gluten, but new research, published in The EMBO Journal, points to novel therapeutic targets that may soon lead to effective treatments.
The study was led by Luigi Maiuri, of the San Raffaele Scientific Institute in Milan, Italy, as well as by Valeria Raia, from the University of Naples Federico II in Italy and Guido Kroemer, from Paris Descartes University in France.

Protein key in cystic fibrosis, celiac disease
Maiuri explains the starting point of the research, noting that the prevalence of celiac disease is roughly three times higher among people with cystic fibrosis — a condition in which a thick layer of mucus builds up in the lungs and intestines.

"This co-occurrence made us wonder if there is a connection between the two diseases at the molecular level," says Maiuri.
As the researchers explain, cystic fibrosis is caused by mutations in a gene that encodes a protein called cystic fibrosis transmembrane conductance regulator (CFTR).

CFTR is an ion transport protein that keeps the mucus fluid. When this protein is faulty, the mucus becomes sticky and cloggy.
Genetic mutations in CFTR also activate the immune system, triggering a range of reactions in the lungs and intestines.
Such changes resemble the effects of gluten in people with celiac disease, so the team set out to study the molecular chain reactions in detail, hoping to discover what was behind the similarities.

The researchers studied human cell lines from people intolerant to gluten and found that a peptide called P31-43 binds to CFTR, inhibiting its function. This resulted in cellular stress and inflammation.

The findings indicate that CFTR is crucial in gluten sensitivity
Bron: Medical news Today

EMBO is an organization of more than 1800 leading researchers that promotes excellence in the life sciences. The major goals of the organization are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information, and help build a European research environment where scientists can achieve their best work

A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease

Valeria R Villella1, Andrea Venerando2, Giorgio Cozza3, Speranza Esposito1, Eleonora Ferrari1,4, Romina Monzani1,4, Mara C Spinella1,4,
Vasilis Oikonomou5, Giorgia Renga5, Antonella Tosco6, Federica Rossin7, Stefano Guido8, Marco Silano9, Enrico Garaci10, Yu‐Kai Chao11,
Christian Grimm11, Alessandro Luciani12, Luigina Romani4, Mauro Piacentini7,13, Valeria Raia6,†, Guido Kroemer (*,14,15,16,17,18,19,† and Luigi Maiuri (*,1,4,†

1 European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy
2 Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy
3 Department of Molecular Medicine, University of Padova, Padova, Italy
4 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
5 Department of Experimental Medicine, University of Perugia, Perugia, Italy
6 Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University Naples, Naples, Italy
7 Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
8 Department of Chemical, Materials and Production Engineering, Federico II University Naples, Naples, Italy
9 Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Roma, Italy
10 University San Raffaele and 21 IRCCS San Raffaele, Rome, Italy
11 Department of Pharmacology and Toxicology, Faculty of Medicine, University of Munich (LMU), Munich, Germany
12 Institute of Physiology CH, University of Zurich, Zurich, Switzerland
13 National Institute for Infectious Diseases IRCCS “L. Spallanzani”, Rome, Italy
14 Centre de Recherche des Cordeliers, Equipe11 labellisée Ligue Nationale Contrele Cancer, Paris, France
15 Centre de Recherche des Cordeliers, INSERM U1138, Paris, France
16 Université Paris Descartes, Paris, France
17 Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
18 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP‐HP, Paris, France
19 Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
↵* Corresponding auhor. Tel: +33142116046; E‐mail:
    Corresponding auhor. Tel: +393311313941; E‐mail:


Intestinal handling of dietary proteins usually prevents local inflammatory and immune responses and promotes oral tolerance.
However, in ~ 1% of the world population, gluten proteins from wheat and related cereals trigger an HLA DQ2/8‐restricted TH1 immune and antibody response leading to celiac disease.
Prior epithelial stress and innate immune activation are essential for breaking oral tolerance to the gluten component gliadin.

How gliadin subverts host intestinal mucosal defenses remains elusive. Here, we show that the α‐gliadin‐derived LGQQQPFPPQQPY peptide (P31–43) inhibits the function of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel pivotal for epithelial adaptation to cell‐autonomous or environmental stress. P31–43 binds to, and reduces ATPase activity of, the nucleotide‐binding domain‐1 (NBD1) of CFTR, thus impairing CFTR function.

This generates epithelial stress, tissue transglutaminase and inflammasome activation, NF‐κB nuclear translocation and IL‐15 production, that all can be prevented by potentiators of CFTR channel gating. The CFTR potentiator VX‐770 attenuates gliadin‐induced inflammation and promotes a tolerogenic response in gluten‐sensitive mice and cells from celiac patients.
Our results unveil a primordial role for CFTR as a central hub orchestrating gliadin activities and identify a novel therapeutic option for celiac disease

Figure 3.
Mutual relationship between gliadin, TG2, and CFTR in intestinal epithelial cells

Figure 6.
Schematic view of celiac disease pathogenesis

Alle figuren - zie

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