FAS engagement drives apoptosis of enterocytes of coeliac patients

Abstract

Background-Villus atrophy is the most distinctive sign of untreated coeliac disease (CD) and epithelial apoptosis is considered to be involved in this stage of the coeliac lesion. The extent of villus atrophy is, however, not homogeneous and patients with patchy or mild lesions have been described. Aims-To address: (a) the degree of "patchiness" in untreated CD patients; and (b) to clarify if apoptosis, and eventually which trigger drives it, causes epithelial damage. Patients-Twenty of 40 untreated, 14 treated coeliac patients, and 15 controls received five or more multiple duodenal biopsies; the remaining 20 untreated CD patients had no more than three biopsies. Methods-All biopsies were analysed to monitor the presence of a "flat" mucosa. Biopsies of 14 untreated, 10 treated coeliacs, and seven controls were cultured with or without gliadin. DNA fragmentation was studied by terminal deoxynucleotidyl transferase (TdT) mediated dUTP digoxigenin nick end labelling (TUNEL), and FAS and Ki67 expression by immunohistochemistry. Antiendomysium antibodies (EMA) were surveyed in biopsy culture supernatants. Results-A pattern of patchy duodenal lesions was observed in all untreated CD patients biopsied up to five times. High enterocyte FAS expression, and a high number of TUNEL+ and Ki67+ enterocytes were detected in areas with villus atrophy but not in those with a normal morphology (p<0.001). Conversely, EMA in culture supernatants and signs of immunological activation were present in all untreated CD biopsies. In vitro gliadin challenge increased the number of TUNEL+ and Ki67+ enterocytes (p<0.001 v cultures with medium alone) only in "flat" biopsies. Neutralising anti-FAS monoclonal antibodies were found to control gliadin induced enterocyte apoptosis (p>0.01) while agonist anti-FAS monoclonal antibody increased it (p<0.001). Conclusions-Patchy lesions are observed in untreated CD mucosa and epithelial FAS engagement is a key trigger in driving villus atrophy in CD. (Gut 2001;48:418-424)

Enhanced Expression of Interferon Regulatory Factor-1 in the Mucosa of Children with Celiac Disease

“…In this context, it could participate in the complex pattern of events that eventually lead to the villous atrophy. Indeed, recent studies have highlighted the role of FAS-mediated apoptosis in the gliadinmediated induction of mucosal damage (39). Finally, it should be pointed that IRF-1 trans-activating IL-15 could also participate to the development of CD94 ϩ natural killer T cells, which heavily infiltrate the CD mucosa (18,40,41).…”

NF-κB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145

“…45,47,48 The up-regulation of death effector molecules, such as fas ligand, is of particular significance in that increased oxidative stress, as occurs in GVHD, induces the expression of fas on intestinal epithelial cells. 49,50 Thus, bortezomib may induce gut toxicity by increasing the susceptibility of intestine cells to immune-mediated death by fas/fas ligand interactions with alloactivated T cells.…”

Celiac Disease: a model autoimmune disease with gene therapy applications

“…38 These cells are phenotypically and functionally different from the lamina propria CD4+ gliadin specific T cells, as they contain a mixture of TCR gd+ T cells, they are not CD4+ and also at least a subgroup expresses the CD94 markers. 39,40 Several studies addressed the function of IEL in disease progression, but no definitive consensus on their role in the pathogenesis of CD has emerged, although it is clear that they might be involved in epithelial damage, a key aspect of CD, 39 via epithelial engagement of FAS via FAS-L, and thus activation of the death receptor expressed on epithelia, 41 perforin release, 42 and possible recognition of Class I-like molecules expressed by 'stressed' epithelial cells. 43 There is agreement, however, that their migration ( Figure 2) and activation at the level of the intraepithelial compartment is controlled by the local release of IL-15.…”