Everything to know about celiac disease and its complications

Celiac disease has been at the heart of Nadine Cerf-Bensussan’s research for several years and for good reason, this Inserm research director, head of a lab at Imagine is a specialist in the connections between the immune system and the bowel. Considered today as a key part in our immunity, the bowel has been neglected for a long time by immunologists and yet with its 50m², by its surface area, it is the first barrier with the outside world. It forms a complex ecosystem made up of billions of bacteria, the famous microbiota, which develops after birth and for which the composition is largely influenced by our diet and many other environmental factors. As soon as the cooperation between the cells lining the intestinal wall and the immune system cells deteriorates, there is a high risk of inflammation or any other damage, as shown in celiac disease. 

Celiac disease: a poorly diagnosed disease

It is estimated that 1% of the Caucasian population is affected by celiac disease, or gluten intolerance. In France, 0.5% to 1% of the population would be affected, which is 300,000 to 600,000 people. “Like for other inflammatory and chronic diseases and based on studies conducted worldwide, the incidence has probably been increased between 2 to 4 times over the last 50 years” points out Nadine Cerf-Bensussan. However, there are geographic variations depending on genetic factors and gluten consumption. 

The diagnosis is relatively simple and consists of a blood analysis to detect the levels of anti-tissue transglutaminase antibodies followed by confirmation with an intestinal endoscopy to show typical intestinal damage and villous atrophy, which does not stop celiac disease from being largely underdiagnosed.

Today, the disease mechanism is well understood. It is related to the destruction of the intestinal mucosa by the immune system, reducing the digestive functions of the bowel and explaining the symptoms of the disease. These folds which cover the bowel increase the surface area for absorbing nutrients; their disappearance causes most of the symptoms of celiac disease, namely chronic diarrhea, recurrent abdominal pains, bloating, weight loss, anemia sometimes with extraintestinal manifestations. These problems can be accompanied by osteoporosis, rheumatism, dermatitis herpetiformis, neurological manifestations, infertility, but also autoimmune diseases type I diabetes and thyroiditis. 

Celiac disease: an autoimmune disease

Celiac disease is caused by an inappropriate response of the immune system to gluten proteins. Gluten corresponds to the insoluble fraction of wheat, barley, rye and spelt flours in water. It forms this viscoelastic mass that we get by mixing flour with water and which is used to make bread, pasta and cakes. “Proteins in gluten are partially digested by the bowel in the form of peptides, which can penetrate the intestinal wall and in people with celiac disease, activate an immune response,” explains Nadine Cerf-Bensussan. However, this reaction is only observed in people who are genetically susceptible and are carriers of the HLA-DQ2 and HLA-DQ8 molecules. These two proteins help present gluten peptides to immune system cells and more particularly to lymphocytes T CD4+. The cooperation between these lymphocytes T CD4 activated by gluten and a soluble factor produced in excess in the patient’s bowel, IL-15, leads to the activation of natural killer cells (CD8), capable of destroying the intestinal epithelium.

“However, there are still many questions about the mechanisms that lead to the onset of the disease in just a small fraction of those who are susceptible. The current work is looking at the role of additional or environmental genetic factors, particularly viral infections. The role of the microbiota is also mentioned, but it is still poorly understood” completes the researcher.

One treatment: a strict gluten free diet

To date, the only known effective treatment for celiac disease is a strict gluten free diet for life. It helps symptoms and antibodies to disappear and gradually restores the intestinal mucosa. However, the gluten free diet should only start once the diagnosis has been clearly made because of the disappearance of antibodies. Indeed, it becomes difficult to establish after the diet has started. 

This very restrictive diet is poorly followed by 40% of patients, creating an increase in the amount of work to identify drug therapies. Several avenues are being studied, but they have not yet demonstrated their effectiveness.

When the disease is resistant to a gluten free diet

In about 0.5% of patients, intestinal damage is not healed even though a very strict gluten free diet is followed, which indicates the occurrence of refractory celiac disease. Work carried out by Nadine Cerf-Bensussan’s team in close collaboration with the CELAC network has contributed to clarifying the mechanisms of resistance in refractory celiac disease. In half of these patients, resistance to the diet revealed a lymphoma, which firstly develops discreetly, then can turn into an invasive lymphoma with a very poor prognosis.

Thanks to research, the immune cell at the origin of the lymphoma has been identified, which helps to provide markers that facilitate the diagnosis of these lymphomas. It has also been shown that malignant cells acquire mutations in signaling pathways (JAK1/STAT3), which favor their growth in inflammatory intestinal tissue, and particularly their response to IL-15. This work suggests several therapeutic avenues being studied.

In the last few years, considerable progress has been made in deciphering the mechanisms of celiac disease and one of its most serious complications, refractory celiac disease. They have helped review all therapeutic avenues being explored, aiming to both replace the diet in uncomplicated celiac disease and treat resistant forms. The challenge is now proving their benefit for patients.

Maladie cœliaque : une maladie immunitaire

La maladie cœliaque est due à une réponse inappropriée du système immunitaire face aux protéines du gluten. Le gluten correspond à la fraction insoluble dans l’eau des farines de blé, d’orge, de seigle, d’épeautre. Il forme cette masse visco-élastique que l’on obtient en mélangeant la farine avec de l’eau et qui sert à faire le pain, les pâtes et les gâteaux. « Les protéines présentes dans le gluten sont partiellement digérées par l’intestin sous forme de peptides qui peuvent pénétrer la barrière intestinale et chez les personnes souffrant de maladie cœliaque, activer une réponse immunitaire, » explique Nadine Cerf-Bensussan. Toutefois cette réaction n’est observée que chez les personnes génétiquement prédisposées et porteuses des molécules HLA-DQ2 et HLA-DQ8. Ces deux protéines permettent de présenter les peptides du gluten aux cellules du système immunitaire et plus particulièrement aux lymphocytes T CD4+. La coopération entre ces lymphocytes T CD4 activées par le gluten et un facteur soluble produit en excès dans l’intestin des patients, IL-15, conduit à l’activation de cellules tueuses (CD8), capables de détruire l’épithélium intestinal.

« De nombreuses interrogations demeurent toutefois quant aux mécanismes qui conduisent au déclenchement de la maladie seulement chez une petite fraction des sujets prédisposés. Les travaux en cours recherchent le rôle de facteurs génétiques complémentaires ou environnementaux en particulier des infections virales. Le rôle du microbiote est aussi évoqué, mais reste mal compris » complète la chercheuse.

Un seul traitement la suppression du gluten

A ce jour, le seul traitement efficace et reconnu de la maladie cœliaque est un régime sans gluten strict à vie. Il permet la disparition des symptômes, des anticorps et une restauration progressive de la muqueuse intestinale. Le régime sans gluten ne doit toutefois débuter qu’une fois le diagnostic clairement établi du fait de la disparition des anticorps, il devient en effet difficile à établir après régime.  

Ce régime très contraignant serait mal suivi par plus de 40 % des patients suscitant un nombre croissant de travaux pour identifier des traitements médicamenteux. Plusieurs pistes sont à l’étude, mais elles n’ont pas encore fait la preuve de leur efficacité.

Quand la maladie est résistante au régime sans gluten

Chez environ 0,5 % des patients, les lésions intestinales ne guérissent pas malgré un régime sans gluten très strictement suivi indiquant l’apparition d’une maladie cœliaque réfractaire. Les travaux réalisés par l’équipe Nadine Cerf-Bensussan, en étroite collaboration avec le réseau CELAC, ont contribué à élucider les mécanismes de résistances dans les maladies cœliaques réfractaires. Chez la moitié des patients, la résistance au régime révèle un lymphome qui évolue d’abord à bas bruit puis peut se transformer en un lymphome invasif de très mauvais pronostic.

Grâce à la recherche, la cellule immune à l’origine du lymphome a pu être identifiée, ce qui a permis de proposer des marqueurs facilitant le diagnostic de ces lymphomes. Il a aussi été montré que les cellules malignes acquièrent des mutations dans des voies de signalisation (JAK1/STAT3) qui favorisent leur expansion dans le tissu inflammatoire intestinal, et notamment leur réponse à l’IL-15. Ces travaux suggèrent plusieurs pistes thérapeutiques en cours d’étude.

Ces dernières années, des progrès considérables ont été effectués dans le décryptage des mécanismes de la maladie cœliaque et d’une de ses complications les plus graves, la maladie cœliaque réfractaire. Ils ont permis de faire le point sur l’ensemble des pistes thérapeutiques en cours d’exploration visant les unes à remplacer le régime dans la maladie cœliaque non compliquée, les autres à traiter les formes résistantes. Le défi est désormais de démontrer leur bénéfice pour les patients.