Intestinal digestive resistance of immunodominant gliadin peptides.
Two recently identified immunodominant epitopes from alpha-gliadin account for most of the stimulatory activity of dietary gluten on intestinal and peripheral T lymphocytes in patients with celiac sprue. The proteolytic kinetics of peptides containing these epitopes were analyzed in vitro using soluble proteases from bovine and porcine pancreas and brush-border membrane vesicles from adult rat intestine. We showed that these proline-glutamine-rich epitopes are exceptionally resistant to enzymatic processing. Moreover, as estimated from the residual peptide structure and confirmed by exogenous peptidase supplementation, dipeptidyl peptidase IV and dipeptidyl carboxypeptidase I were identified as the rate-limiting enzymes in the digestive breakdown of these peptides. A similar conclusion also emerged from analogous studies with brush-border membrane from a human intestinal biopsy. Supplementation of rat brush-border membrane with trace quantities of a bacterial prolyl endopeptidase led to the rapid destruction of the immunodominant epitopes in these peptides. These results suggest a possible enzyme therapy strategy for celiac sprue, for which the only current therapeutic option is strict exclusion of gluten-containing food.
Hausch
Felix
F
Department of Chemical Engineering, Stanford University, Stanford, California 94305-5025, USA.
Shan
Lu
L
Santiago
Nilda A
NA
Gray
Gary M
GM
Khosla
Chaitan
C
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D004063:Digestion; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005903:Gliadin / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000648:ultrastructure; D007421:Intestine, Small / Q000648:ultrastructure; D008871:Microvilli / Q000378:metabolism; D010179:Pancreas / Q000201:enzymology; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D000085822:Prolyl Oligopeptidases; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism; D013379:Substrate Specificity; D013552:Swine
D000939:Epitopes; D010455:Peptides; D005903:Gliadin; D010450:Endopeptidases; D018819:Dipeptidyl Peptidase 4; C020071:dipeptidyl carboxypeptidase; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases