Coeliac disease is an autoimmune disease triggered in genetically predisposed individuals by gluten adsorption (gluten is a ubiquitous component of cereals and as such is broadly found in many foods). In genetically susceptible individuals, gluten ingestion results in intestinal mucosa damage and malabsorption of essential nutrients. As of today, a life-long gluten-free diet is the only therapy available. Preliminary data obtained during the last few years have shown that the prevalence of coeliac disease is more frequent in the European population than originally estimated from the clinical symptomatology. The cluster project is devoted to better appreciate at the EU level the prevalence of the disease under its different symptomatic forms, to decipher the genetic components of the disease and to study the pathogenesis of the disease by testing the molecular hypothesis built on the most recent immunological discoveries.
The Coeliac-EU cluster groups together three research projects with complementary principal scientific objectives:
- To establish the prevalence of coeliac disease in a large European population;
- To characterise the genetic basis of this common food intolerance;
- To identify factors involved in the gluten-triggered pathogenesis of mucosal damage.
The EPIDEMIOLOGY study will provide an estimate of the prevalence of coeliac disease in Europe and allow identification and early treatment of 'silent' coeliac people who are so far not detected. The detection relies on two anti-tissue transglutaminase test kits, one based on guinea-pig and one on human. The detection kits have been extensively studied and validated in ring tests. At this stage, the human based test looks slightly more specific than the guinea-pig-based test, with comparable sensitivity. The large-scale comparative evaluation will be started as soon as the gathering of the retrospective sera will be completed. 5.766 retrospective sera have already been sampled. 13.400 new sera have already been collected for the prevalence determination study, which has already started in advance of the timetable. Self-administered questionnaires for the antibody positive individuals will allow recording of the basic data of signs and symptoms of these individuals, which will be valuable information when describing the results of the study.
The GENETIC study will identify association(s) between gene(s) and the coeliac disease as well as clarify the contribution of the HLA genetic components and their association with other (non-HLA) genetic markers. DNA samples from 623 simplex families and 548 sib-pair families have been assembled. Two-third of the HLA typing was carried out. Fine HLA typing of the DQ2 negative group is proceeding in each of the five centres and is already finished in some of those.
The PATHOGENESIS study will characterise features of damage in the coeliac mucosa and provide information on factors involved in the pathogenesis of mucosal damage, in particular on T cells involvement. The cytokine pattern in the organ culture system of the treated coeliac mucosa has been refined: the dominance of gamma interferon indicate a strongly Th1 polarised response to gluten. Molecules candidate to drive such a response are IL15, IL18 and possibly €-interferon. Induction of epithelial cells apoptosis as an early gluten triggered response has been demonstrated to involve FAS. This appears to be an essential factor in the pathogenic process leading to mucosal damage. Genes sequences up and down regulated by transforming growth factor-beta in the fibroblasts-epithelial cell co-culture model have been isolated and studied. Their relevance in the apoptotic process is suggestive but remain to be directly demonstrated.
A new simple serological diagnostic test, suitable for large population screening and allowing an easier and earlier detection of the disease, will be validated. A non-invasive genetic test based on DNA analysis may potentially be developed in the future. New therapeutic strategies, for instance based on immunomodulation, may potentially be developed in the future.