Increased enterocyte apoptosis and Fas-Fas ligand system in celiac disease.
Our aim was to evaluate whether increased enterocyte apoptosis was responsible for mucosal flattening in celiac disease (CD), and, since the mechanisms responsible for tissue injury in this condition are unknown, we studied the possibility that the Fas-Fas ligand (FasL) system may be involved. Endoscopic duodenal biopsy specimens from 12 patients with untreated and 12 with treated CD and 12 control subjects were evaluated for enterocyte apoptosis by the terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick-end labeling assay and for Fas and FasL expression by immunohistochemistry. A coculture of isolated enterocytes (targets) and purified lamina propria mononuclear cells (LPMCs) (effectors) was performed in the absence or presence of an antagonistic ZB4 anti-Fas antibody. We found a significant correlation between the degree of villous atrophy, morphometrically evaluated, and the level of enterocyte apoptosis, suggesting that mucosal flattening is a consequence of exaggerated epithelial cell death. Most celiac enterocytes express Fas, and LPMCs express FasL. The abolishment of enterocyte apoptosis observed in the presence of ZB4 antibody suggests that enterocytes are potential targets of lymphocyte infiltrate. These results directly demonstrate that FasL-mediated apoptosis is a major mechanism responsible for enterocyte death in CD.
Ciccocioppo
R
R
Department of Internal Medicine, University of L'Aquila, L'Aquila, Italy.
Di Sabatino
A
A
Parroni
R
R
Muzi
P
P
D'Alò
S
S
Ventura
T
T
Pistoia
M A
MA
Cifone
M G
MG
Corazza
G R
GR
D000328:Adult; D000368:Aged; D017209:Apoptosis; D001345:Autoradiography; D001706:Biopsy; D002446:Celiac Disease / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D002518:Ceramides / Q000032:analysis; D018920:Coculture Techniques; D004384:Duodenoscopy; D004386:Duodenum / Q000473:pathology; D020895:Enterocytes / Q000166:cytology / Q000502:physiology*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D017493:Leukocyte Common Antigens / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D019014:fas Receptor / Q000502:physiology*
D002518:Ceramides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D017493:Leukocyte Common Antigens