Mechanism of Villous Atrophy in Celiac Disease: Role of Apoptosis and Epithelial Regeneration

Abstract

Context.—The data on status of apoptosis in patients with celiac disease are conflicting. Furthermore, complex interaction between intrinsic and common apoptotic pathways, apoptotic inhibitors, and epithelial cell proliferation is largely unclear for patients with celiac disease. Objectives.—To determine the role of apoptosis and epithelial cell regeneration in celiac disease. Design.—Twenty-five treatment-naïve patients with celiac disease and 6 patients with functional dyspepsia, as controls, were included and duodenal biopsy specimens from all were subjected to immunohistochemistry with markers of intrinsic apoptotic pathway (AIF, H2AX, p53), common pathway (CC3, M30), apoptotic inhibitors (XIAP, Bcl2), and epithelial proliferation (Ki-67). Apoptotic and proliferation indices were calculated. Results.—Expression of end-apoptotic products, that is, H2AX in the cell nuclei (P = .01) and M30 in the cell cytoplasm (P < .01), was significantly upregulated in celiac disease in comparison to controls. Cleaved caspase-3 was also upregulated in villous cytoplasm in celiac disease. Apoptotic inhibitor Bcl2 was significantly down-regulated in celiac disease in comparison to controls. In addition, Ki-67 proliferation index was upregulated both in the crypts and villous mucosal epithelium in comparison to the crypts of the controls. Conclusions.—Treatment-naïve patients with celiac disease have significantly higher level of apoptosis that involves both the common and intrinsic apoptotic pathways. Increased apoptosis and unequaled cell regeneration in crypts probably results in villous atrophy. Down-regulation of apoptotic inhibitors in treatment-naïve celiac disease imparts an additional pro-apoptotic effect.

Glucopsychosine increases cytosolic calcium to induce calpain-mediated apoptosis of acute myeloid leukemia cells

“…In AML cells with high basal calpain levels and reduced calpastatin, additional activation of these enzymes could overcome a threshold and induce apoptosis. This is seen in other disease states characterized by elevated basal caspase 3 levels (i.e., Breast cancer, Parkinson's disease and Celiac disease) where the application of a death stimulus results in caspase-dependent cell death [76][77][78]. We therefore propose a similar mechanism whereby glucopsychosine's mechanism of AML selectivity is also related to its ability to further activate calpain enzymes resulting in apoptotic cell death.…”

Architectural and functional alterations of the small intestinal mucosa in classical Whipple's disease

“…Mucosal architecture depends on the balance between apoptosis of mature surface enterocytes and production of undifferentiated enterocytes within the crypts. 12 Accordingly, we observed an increased number of epithelial apoptotic cells with clustering at the villus tips and increased numbers of Ki-67-positive proliferating crypt cells in untreated as well as treated CWD patients (Figure 1a and c). Furthermore, visualization of epithelial alkaline phosphatase, which is a generally accepted marker of small intestinal mucosal differentiation, revealed a strong reduction in alkaline phosphatase expression in the surface epithelial cells in untreated CWD patients ( Figure 1a).…”

CELF1/p53 axis: a sustained antiproliferative signal leading to villus atrophy under total parenteral nutrition

“…We speculate that environmental differences between jejunum and ileum, such as bile acids or microbiota, may serve as the influencing factors, and thus these issues are of great interest to be elucidated in future studies. Importantly, however, although the role of aberrant p53 expression in the pathogenesis of villus atrophy has been confirmed in a variety of intestinal diseases/disorders (52,53), the question is by which mechanism is intestinal CELF1, which regulates p53, upregulated by TPN. Given that TPN is a situation that comprises deprivation of enteral nutrition as well as administration of parenteral nutrition (PN), we speculate that both may lead to CELF1 overexpression because of the following 2 lines of evidence.…”