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Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease.
- Source :
-
Gastroenterology [Gastroenterology] 2015 Sep; Vol. 149 (3), pp. 681-91.e10. Date of Electronic Publication: 2015 May 19. - Publication Year :
- 2015
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Abstract
- Background & Aims: The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to the activation of intraepithelial cytotoxic T cells and the development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who were without any signs of adaptive antigluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in the absence of villous atrophy.<br />Methods: We collected blood and intestinal biopsy specimens from 268 patients at tertiary medical centers in the United States and Italy from 2004 to 2012. All subjects had normal small intestinal histology. Study groups included healthy individuals with no family history of celiac disease or antibodies against tissue transglutaminase 2 (controls), healthy family members of patients with celiac disease, and potential celiac disease patients. Intraepithelial cytotoxic T cells were isolated and levels of inhibitory and activating natural killer (NK) cells were measured by flow cytometry. Levels of heat shock protein (HSP) and interleukin 15 were measured by immunohistochemistry, and ultrastructural alterations in intestinal epithelial cells (IECs) were assessed by electron microscopy.<br />Results: IECs from subjects with a family history of celiac disease, but not from subjects who already had immunity to gluten, expressed higher levels of HS27, HSP70, and interleukin-15 than controls; their IECs also had ultrastructural alterations. Intraepithelial cytotoxic T cells from relatives of patients with celiac disease expressed higher levels of activating NK receptors than cells from controls, although at lower levels than patients with active celiac disease, and without loss of inhibitory receptors for NK cells. Intraepithelial cytotoxic T cells from potential celiac disease patients failed to up-regulate activating NK receptors.<br />Conclusions: A significant subset of healthy family members of patients with celiac disease with normal intestinal architecture had epithelial alterations, detectable by immunohistochemistry and electron microscopy. The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease.<br /> (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Autoantibodies blood
Case-Control Studies
Celiac Disease blood
Celiac Disease pathology
Epithelial Cells metabolism
Epithelial Cells ultrastructure
GTP-Binding Proteins immunology
HSP27 Heat-Shock Proteins immunology
HSP27 Heat-Shock Proteins metabolism
HSP70 Heat-Shock Proteins immunology
HSP70 Heat-Shock Proteins metabolism
Heat-Shock Proteins
Humans
Interleukin-15 immunology
Interleukin-15 metabolism
Intestinal Mucosa metabolism
Intestinal Mucosa ultrastructure
Intestine, Small metabolism
Intestine, Small ultrastructure
Italy
Molecular Chaperones
Phenotype
Protein Glutamine gamma Glutamyltransferase 2
Risk Factors
Signal Transduction
T-Lymphocytes, Cytotoxic metabolism
T-Lymphocytes, Cytotoxic ultrastructure
Transglutaminases immunology
United States
Adaptive Immunity
Celiac Disease immunology
Cell Communication
Epithelial Cells immunology
Intestinal Mucosa immunology
Intestine, Small immunology
Stress, Physiological
T-Lymphocytes, Cytotoxic immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 149
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 26001928
- Full Text :
- https://doi.org/10.1053/j.gastro.2015.05.013