Broad MICA/B expression in the small bowel mucosa: a link between cellular stress and celiac disease

PLoS One. 2013 Sep 13;8(9):e73658. doi: 10.1371/journal.pone.0073658. eCollection 2013.

Abstract

The MICA/B genes (MHC class I chain related genes A and B) encode for non conventional class I HLA molecules which have no role in antigen presentation. MICA/B are up-regulated by different stress conditions such as heat-shock, oxidative stress, neoplasic transformation and viral infection. Particularly, MICA/B are expressed in enterocytes where they can mediate enterocyte apoptosis when recognised by the activating NKG2D receptor present on intraepithelial lymphocytes. This mechanism was suggested to play a major pathogenic role in active celiac disease (CD). Due to the importance of MICA/B in CD pathogenesis we studied their expression in duodenal tissue from CD patients. By immunofluorescence confocal microscopy and flow cytometry we established that MICA/B was mainly intracellularly located in enterocytes. In addition, we identified MICA/B(+) T cells in both the intraepithelial and lamina propria compartments. We also found MICA/B(+) B cells, plasma cells and some macrophages in the lamina propria. The pattern of MICA/B staining in mucosal tissue in severe enteropathy was similar to that found in in vitro models of cellular stress. In such models, MICA/B were located in stress granules that are associated to the oxidative and ER stress response observed in active CD enteropathy. Our results suggest that expression of MICA/B in the intestinal mucosa of CD patients is linked to disregulation of mucosa homeostasis in which the stress response plays an active role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Celiac Disease / genetics*
  • Celiac Disease / metabolism
  • Celiac Disease / pathology
  • Child, Preschool
  • Duodenum / metabolism*
  • Duodenum / pathology
  • Enterocytes / metabolism
  • Enterocytes / pathology
  • Female
  • Gene Expression
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Plasma Cells / metabolism
  • Plasma Cells / pathology
  • Severity of Illness Index
  • Stress, Physiological / genetics*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology

Substances

  • Histocompatibility Antigens Class I
  • MHC class I-related chain A
  • MICB antigen

Grants and funding

The funders, Fundacion Ciencias Exactas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.