Celiac disease is a chronic condition of the upper small intestine caused by an immune response directed at gluten, a complex of proteins present in wheat, oats, and barley. Elimination of gluten from the diet restores normal gut function, but to date no approach for desensitization to gluten has been developed, so gluten ingestion must be avoided throughout life. The pathology of celiac disease is characterized by the loss of the slender, fingerlike villi formed by the intestinal epithelium (a condition termed villous atrophy), together with an increase in the size of the sites in which epithelial cells are renewed (crypt hyperplasia) (Fig. 14.24). These pathological changes result in the loss of the mature epithelial cells that cover the villi and normally absorb and digest food, and are accompanied by severe inflammation of the intestinal wall, with increased numbers of T cells, macrophages, and plasma cells in the lamina propria, as well as increased numbers of lymphocytes in the epithelial layer. Gluten seems to be the only food component that provokes intestinal inflammation in this way, a property that reflects gluten’s ability to stimulate both innate and specific immune responses in genetically susceptible individuals. The incidence of celiac disease has increased fourfold in the past 60 years, correlating with changes in baking practice that include adding large amounts of extra gluten to dough to decrease the time required for the dough to rise and to improve the texture.
Celiac disease shows an extremely strong genetic predisposition, with more than 95% of patients expressing the HLA-DQ2 class II MHC allele. In mono-zygotic twins, if one twin develops it, there is an 80% probability that the other will, but only a 10% concordance is observed in dizygotic twins. Nevertheless, most individuals expressing HLA-DQ2 do not develop celiac disease despite the almost universal presence of gluten in the Western diet. Thus, other genetic or environmental factors must make important contributions to susceptibility.
Peptides naturally produced from gluten do not bind to MHC class II molecules FasIFN-˜An enzyme, tissue transglutaminase (tTG), modiÿes the peptides so they now can be processed and bind to the MHC class II molecules The bound peptide activates gluten-speciÿc CD4 T cells FasLtTGThe activated T cells can kill mucosal epithelial cells by binding Fas. They also secrete IFN-˜, which activates the epithelial cell to produce cytokines and chemokines that recruit other in°ammatory cells
Fig. 14.25 Molecular basis of immune recognition of gluten in celiac disease. After the digestion of gluten by gut digestive enzymes, deamidation of epitopes by tissue transglutaminase renders the gluten more susceptible to being readily processed by local antigen-presenting cells, ultimately leading to its binding to HLA-DQ molecules and priming of the immune system.