Coeliac disease is a common disorder in western societies, affecting about one in every 200 individuals. Although the disease is sometimes spotted in childhood, in which case symptoms include diarrhoea and malabsorption, it often remains undiagnosed, or is misdiagnosed, until later on in life. In adults, there is a wider spectrum of symptoms than in children. Some individuals have no subjective symptoms at all, whereas others might have any or a mixture of a range of symptoms including anaemia, fatigue, osteoporosis, depression, and infertility, none of which are especially suggestive of a disorder of the gut. Coeliac disease is over-represented in patients with other autoimmune disorders, in particular type-1 diabetes and thyroiditis. Screening for the disorder in these patient groups is, thus, recommended. Whether or not the general population should be screened is, however, questionable. Coeliac disease is caused by an inappropriate immune response to dietary wheat gluten and similar proteins in rye and barley. Development of lesions typical of the disease in the small intestine is dependent on the interplay between genetic and environmental factors. We know some of these factors. Gluten, for example, is obviously an important environmental factor; when this protein is eliminated from the diet, the disease almost invariably goes into complete remission. Indeed, a lifelong gluten-free diet is the standard treatment regimen. A high degree of familial clustering also suggests the importance of heritable factors, but our understanding of the genetics of the disease is incomplete. Many genes probably contribute to disease development, but so far evidence for involvement only exists for HLA-DQ and CTLA4. The HLA-DQA1*05 and HLA-DQB1*02 genes, which are carried by most patients with coeliac disease, encode HLA-DQ2. This molecule binds and presents peptide fragments of gluten proteins to CD4+ T cells (T helper cells) in the coeliac mucosal lesion, activating them. T-cell activation initiates a cascade of events that eventually leads to villous atrophy and crypt cell hyperplasia. Researchers are still trying to determine whether the CTLA4 gene itself confers susceptibility in coeliac disease, or a closely located gene. What is clear, however, is that the effect attributable to this gene is modest compared with that of HLA. Such modest genetic effects are a shared feature of the non-HLA susceptibility genes, but altogether their genetic contribution exceeds that of HLA. CTLA4 is an interesting genetic factor in coeliac disease, since the CTLA4 molecule influences T-cell activation. This action corresponds well with the notion that activation of gluten-specific T cells is an important checkpoint in the development of the disease. Over the past few years, scientists have identified which of several distinct gluten peptides are recognised by T cells of coeliac lesions. Most lesion-derived T cells, at least in adults, recognise gluten peptides that are modified by transglutaminase, an enzyme in the mucosa. Modification of gluten by tissue transglutaminase is, therefore, probably a key event in the development of coeliac disease. The modified peptides bind better to HLA-DQ2, and are possibly presented to the gut T cells in a manner that prevents establishment, or maintenance, of oral tolerance to gluten. The presence of autoantibodies to tissue transglutaminase (endomysium antibodies) is strongly indicative of coeliac disease. The role of the enzyme in T-cell epitope formation and the production of the autoantibodies are probably related events. At the moment, the gluten status of food is determined by the presence or absence of gluten peptides. However, now that we are aware that different types of peptides exist, testing can become much more precise than before. As our understanding of coeliac disease improves, treatment options will present themselves. We are indebted, as scientists, to the patients who have agreed to endoscopies or who have otherwise aided us in our research. We remain confident that the ongoing research will eventually improve the life of the many people who have this disorder. Our understanding of the pathogenesis of coeliac disease is already more advanced than that of other chronic inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. We understand the function of key elements of the disease, now we have to concentrate on getting to grips with coeliac disease as a whole. This young boy enjoys his piece of bread Consumption of bread is part of our culture, but many people are intolerant to wheat gluten.
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Apr 1, 2004
M Charrel-Dennis + 6
Open Access
