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.