Increased Enterocyte Apoptosis and Fas-Fas Ligand System in Celiac Disease

Abstract

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.

Defective Expression of Scavenger Receptors in Celiac Disease Mucosa

“…The findings of the present study demonstrate that the active phases of CD are characterized by accumulation of apoptotic cells/bodies in the duodenal mucosa, thus confirming data of previous studies [11,12,13], and diminished expression of macrophage-associated scavenger receptors, which are important in the recognition of exposed phosphatidylserine on the surface of apoptotic cells. In particular, we show that ACD patients have reduced mucosal levels of CD36, TSP-1 and CD61, also known as anb3 integrin or CD51 or vitronectin receptor, which altogether constitute an active complex mediating phagocytosis of apoptotic bodies/debris.…”

Matrix metalloproteinase pattern in celiac duodenal mucosa

“…The demonstration of a significant correlation between the levels of MMP-12 and the degree of villous atrophy points to a pathogenetic relevance of this enzyme. Since a correlation between the magnitude of villous atrophy and that of enterocyte apoptosis has been shown previously in untreated CD patients, 26 it is conceivable that, by degrading either interstitial ECM or basement membranes, 12 MMP-12 ultimately leads to the collapse of villous architecture and subsequent enterocyte shedding to the lumen. Furthermore, since MMP expression is highly dependent on cytokines 27,28 and gluten exposure in patients with CD rapidly elicits high levels of Th-1 cytokines, such as IFN-g, IL-2 and TNF-a, 13,14 we simultaneously determined the levels of IFN-g and TNF-a.…”

Detection of Alkaline Sphingomyelinase Activity in Human Stool: Proposed Role as a New Diagnostic and Prognostic Marker of Colorectal Cancer

“…At the intestinal level in this pathway, the first step, which leads to ceramide and phosphorylcholine generation, is catalyzed mainly by alkaline sphingomyelinase, an enzyme with a high activity not only in the mucosa but also in the lumen, because it may originate from the sloughing of epithelial cells and from the dissociation of the enzyme from the mucosal surface caused by lumenal factors, primarily the bile salts (31). Alkaline sphingomyelinase, by exerting a major role in dietary sphingomyelin digestion, is responsible for the generation of antiproliferative and/or apoptosis sphingolipid messengers, mainly ceramide, which are able to trigger the rapid turnover and apoptosis in intestinal and colon epithelial cells (13,(32)(33)(34)(35)(36). Markedly reduced mucosal alkaline sphingomyelinase activity has been associated with colorectal carcinoma (23), colorectal adenomas (15), familial adenomatous polyposis (24), and Figure 3.…”