BINDING OF GLUTEN PEPTIDES TO THE COELIAC DISEASE-ASSOCIATED HLA-DQ2 MOLECULE BY COMPUTATIONAL METHODS

摘要

Celiac disease (CD) often starts shortly after the first introduction of wheat into the diet. Symptoms include diarrhea, malabsorption, and failure to thrive, which is due to a inefficient uptake of nutrients by a flattening intestinal epithelium. Removal of gluten from the diet, at present the only treatment for the disease, is an effective way to stop the disease process, and reintroduction of gluten in the patient's diet invariably leads to the reappearance of the symptoms '"2. In recent years some different gluten-derived peptides have been identified that are recognized by T cell clones isolated from biopsies of CD patients 3"5. CD is limited to genetically predisposed individuals expressing HLA-DQ2 (DQA 1*0501/61*0201) and/or -DQ8 (DQA1*0301/B 1*0302) heterodimers. The molecular mechanism is considered to involve the DQ2 and DQ8 molecules for binding gluten peptides and presenting them to T cells in the small intestine. Peptide binding to HLA-DQ2 and HLA-DQ8 molecules is most efficient when negatively charged amino acids are present at anchor positions in the peptide. Gluten contains very few negatively charged amino acids, but many glutamines, which may be deamidated to the negatively charged glutamate. This reaction may be catalyzed by the tissue transglutaminase (tTG) enzyme.