Interplay between genetics and the environment in the development of celiac disease: perspectives for a healthy life

Autoimmune diseasesProgress in celiac disease (CD) research has been spectacular in recent years.The nature of gluten-derived peptides that are recognized by gut-derived T cells from patients, and that are therefore likely to be involved in disease development, has been elucidated (1-5).It has further been established that a ubiquitous enzyme modifies such peptides, leading to improved binding of such peptides to HLA-DQ2/8 molecules (6, 7).This now establishes a molecular basis for the well-known association between CD and the expression of these HLA-DQ molecules (8, 9).CD is therefore the best-characterized HLA-associated disease to date.However, several issues remain unclear.Why does the disease develop in only a small percentage of the individuals who carry the predisposing HLA-DQ molecules?Why does this disease severely affect some patients while others have only mild or no clinical symptoms?Can we use our current knowledge to prevent or cure this disease? CD pathogenesisCD is caused by intolerance to gluten, a common protein present in wheat.Recent studies indicate that CD develops in 1 of 200-300 individuals in Western Europe and the USA (10-14).The disease often starts shortly after the first introduction of wheat into the diet.Symptoms include diarrhea, malabsorption, and failure to thrive, as a result of an immunological reaction to gluten in the small intestine, which eventually leads to a flat intestinal epithelium, prohibiting efficient uptake of nutrients.Removal of gluten from the diet is an effective way to stop the disease process.It is, at present, also the only treatment for the disease.Reintroduction of gluten in the patient's diet, even decades later, invariably leads to the reappearance of the symptoms.With few exceptions, CD is limited to genetically predisposed individuals, those who express the HLA-DQ2 (A1*0501/B1*0201) and/or -DQ8 (A1*0301/B1*0302) heterodimers (8, 9).This observation correlates well with the overwhelming evidence that CD is a T cell-mediated immune disease.