title: Unexpected role of surface transglutaminase type II in celiac disease.
abstract: OBJECTIVE
  In celiac disease (CD), transglutaminase type II (TG2) has 2 fundamental roles: (1) as the autoantigen recognized by highly specific autoantibodies and (2) the modifier of pathogenic gliadin T-cell epitopes. It follows that inhibition of TG2 might represent an attractive strategy to curb the toxic action of gliadin. Here we studied the validity of this strategy using the organ culture approach.
  
  
  METHODS
  Duodenal biopsy specimens from 30 treated patients with CD, 33 untreated patients with CD, and 24 controls were cultured with or without gliadin peptides p31-43, palpha-9, and deamidated palpha-9 for 20 minutes, 3 hours, and 24 hours. In 31 patients with CD and 16 controls, TG2 inhibitor R283 or anti-TG CUB 7402 or anti-surface TG2 (6B9) mAbs were used in cultures. T84 cells were also cultured with or without peptides with or without TG inhibitors. Mucosal modifications after culture were assessed by immunofluorescence, in situ detection of TG activity, confocal microscopy, and fluorescence-activated cell sorter analysis.
  
  
  RESULTS
  The enzymatic inhibition of TG2 only controlled gliadin-specific T-cell activation. The binding of surface TG2 contained gliadin-specific T-cell activation and p31-43-induced actin rearrangement, epithelial phosphorylation, and apoptosis, both in organ cultures and T84 cells.
  
  
  CONCLUSIONS
  These data indicate a novel and unexpected biological role for surface TG2 in the pathogenesis of CD suggesting a third role for TG2 in CD. These results have a specific impact for celiac disease, with wider implications indicating a novel biologic function of TG2 with possible repercussions in other diseases.
authors.affiliation: Institute of Child Health, University College London, London, England.
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiuri
authors.forename: Carolina
authors.initials: C
authors.lastname: Ciacci
authors.forename: Ida
authors.initials: I
authors.lastname: Ricciardelli
authors.forename: Loredana
authors.initials: L
authors.lastname: Vacca
authors.forename: Valeria
authors.initials: V
authors.lastname: Raia
authors.forename: Antonio
authors.initials: A
authors.lastname: Rispo
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
authors.forename: Thomas
authors.initials: T
authors.lastname: Issekutz
authors.forename: Sonia
authors.initials: S
authors.lastname: Quaratino
authors.forename: Marco
authors.initials: M
authors.lastname: Londei
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002446:Celiac Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D019204:GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D005903:Gliadin / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007421:Intestine, Small / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009924:Organ Culture Techniques; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013379:Substrate Specificity; D011503:Transglutaminases / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins