The function of tissue transglutaminase in celiac disease.
Celiac disease is a chronic small bowel disorder caused by an abnormal immune response to an array of epitopes of wheat gluten and related proteins of rye and barley in genetically susceptible individuals who express the HLA-DQ2/-DQ8 haplotype. Gluten peptides are efficiently presented by celiac disease-specific HLA-DQ2- and HLA-DQ8-positive antigen presenting cells to CD4(+) T-cells that, once activated, drive a T helper cell type 1 response leading to the development of the typical celiac lesion-villous atrophy, crypt hyperplasia and intraepithelial and lamina propria infiltration of inflammatory cells. Tissue transglutaminase (tTG) is a calcium dependent ubiquitous enzyme which catalyses posttranslational modification of proteins and is released from cells during inflammation. tTG is suggested to exert at least two crucial roles in celiac disease: as a deamidating enzyme, that can enhance the immunostimulatory effect of gluten, and as a target autoantigen in the immune response. Since glutamine-rich gliadin peptides are excellent substrates for tTG, and the resulting deamidated and thus negatively charged peptides have much higher affinity for the HLA-DQ2 and HLA-DQ8 molecules, the action of tTG is believed to be a key step in the pathogenesis of celiac disease. This review is focused on the function of tTG in celiac disease, although it also deals with novel advances in tTG-based therapies.
First Department of Medicine, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy. a.disabatino@smatteo.pv.it
Antonio
A
Di Sabatino
Alessandro
A
Vanoli
Paolo
P
Giuffrida
Ombretta
O
Luinetti
Enrico
E
Solcia
Gino Roberto
GR
Corazza
D001324:Autoantigens / Q000378:metabolism; D002384:Catalysis; D002446:Celiac Disease / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D016503:Drug Delivery Systems; D019204:GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013379:Substrate Specificity / Q000276:immunology; D011503:Transglutaminases / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D001324:Autoantigens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins