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.
Highlights
The MICA/B genes encode proteins that are distantly related to the HLA class I gene products
When samples were grouped according to the histological evaluation into non celiacs with normal architecture, and celiacs with mild, moderate or severe enteropathy, we observed that intestinal mucosa from untreated celiac disease (CD) patients exhibited a higher intensity of MICA/B staining compared to samples from healthy controls
Several changes are observed in the epithelium, including altered enterocyte shape and height, loss of brush border, vacuolation, denudation and loss of epithelia, some of which are the consequence of increased enterocyte apoptosis [25]
Summary
The MICA/B genes encode proteins that are distantly related to the HLA class I gene products. They do not associate with b2microglobulin and are conformationally stable without conventional MHC class I peptides bound. MICA is rapidly up-regulated under different stress conditions such as heat-shock, oxidative stress, transformation and viral infection [1,2,3,4,5]. MICA/B interact with the activating NKG2D receptor which is constitutively expressed on NK cells, CD8+ a/b T cells, peripheral blood and intestinal intraepithelial c/d T cells, and NKT cells. MICA/B have been considered markers of cellular distress that facilitate the elimination of damaged, infected, or transformed cells and serving as an immune surveillance mechanism [7,8,9]
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