Unexpected role of surface transglutaminase type II in celiac disease.
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.
Maiuri
Luigi
L
Institute of Child Health, University College London, London, England.
Ciacci
Carolina
C
Ricciardelli
Ida
I
Vacca
Loredana
L
Raia
Valeria
V
Rispo
Antonio
A
Griffin
Martin
M
Issekutz
Thomas
T
Quaratino
Sonia
S
Londei
Marco
M
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
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins