Structural basis for gluten intolerance in celiac sprue.
Celiac Sprue, a widely prevalent autoimmune disease of the small intestine, is induced in genetically susceptible individuals by exposure to dietary gluten. A 33-mer peptide was identified that has several characteristics suggesting it is the primary initiator of the inflammatory response to gluten in Celiac Sprue patients. In vitro and in vivo studies in rats and humans demonstrated that it is stable toward breakdown by all gastric, pancreatic, and intestinal brush-border membrane proteases. The peptide reacted with tissue transglutaminase, the major autoantigen in Celiac Sprue, with substantially greater selectivity than known natural substrates of this extracellular enzyme. It was a potent inducer of gut-derived human T cell lines from 14 of 14 Celiac Sprue patients. Homologs of this peptide were found in all food grains that are toxic to Celiac Sprue patients but are absent from all nontoxic food grains. The peptide could be detoxified in in vitro and in vivo assays by exposure to a bacterial prolyl endopeptidase, suggesting a strategy for oral peptidase supplement therapy for Celiac Sprue.
D000595:Amino Acid Sequence; D000818:Animals; D002446:Celiac Disease / Q000276:immunology* / Q000628:therapy; D002460:Cell Line; D002523:Edible Grain / Q000737:chemistry; D010450:Endopeptidases / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte; D019204:GTP-Binding Proteins / Q000378:metabolism; D005903:Gliadin / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology*; D007421:Intestine, Small / Q000201:enzymology / Q000276:immunology*; D008213:Lymphocyte Activation; D008871:Microvilli / Q000201:enzymology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D000085822:Prolyl Oligopeptidases; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*; D011503:Transglutaminases / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D010450:Endopeptidases; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D019204:GTP-Binding Proteins