title: Mechanism of villous atrophy in celiac disease: role of apoptosis and epithelial regeneration.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To determine the role of apoptosis and epithelial cell regeneration in celiac disease.
  
  
  METHODS
  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.
authors.affiliation: Department of Gastroenterology and Human Nutrition, the All India Institute of Medical Sciences, New Delhi, India.
authors.forename: D M
authors.initials: DM
authors.lastname: Shalimar
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Das
authors.forename: Vishnubhatla
authors.initials: V
authors.lastname: Sreenivas
authors.forename: Siddhartha Datta
authors.initials: SD
authors.lastname: Gupta
authors.forename: Subrat K
authors.initials: SK
authors.lastname: Panda
authors.forename: Govind K
authors.initials: GK
authors.lastname: Makharia
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D001284:Atrophy; D001706:Biopsy; D053148:Caspase 3 / Q000378:metabolism; D002446:Celiac Disease / Q000473:pathology*; D049109:Cell Proliferation; D002648:Child; D015536:Down-Regulation; D004386:Duodenum / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000473:pathology*; D012038:Regeneration; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D019394:Ki-67 Antigen; D053148:Caspase 3