Format

Send to

Choose Destination
Gastroenterology. 2015 Sep;149(3):681-91.e10. doi: 10.1053/j.gastro.2015.05.013. Epub 2015 May 19.

Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease.

Author information

1
Department of Pediatrics, University of Chicago, Chicago, Illinois.
2
Department of Pediatrics, University of Chicago, Chicago, Illinois; European Laboratory for the Investigation of Food-Induced Disorders, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy; Department of Medicine, University of Chicago, Chicago, Illinois; CEINGE-Biotecnologie Avanzate, Naples, Italy.
3
Sainte-Justine Hospital Research Center, Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Canada.
4
Department of Medicine, University of Chicago, Chicago, Illinois.
5
European Laboratory for the Investigation of Food-Induced Disorders, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy.
6
Department of Health Studies, University of Chicago, Chicago, Illinois.
7
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
8
Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, New York.
9
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
10
Department of Medicine, University of Chicago, Chicago, Illinois; Department of Pathology, University of Chicago, Chicago, Illinois. Electronic address: jturner@bsd.uchicago.edu.
11
Department of Pediatrics, University of Chicago, Chicago, Illinois; Department of Medicine, University of Chicago, Chicago, Illinois. Electronic address: bjabri@bsd.uchicago.edu.

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.

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.

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.

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.

KEYWORDS:

Cytotoxic Intraepithelial Lymphocytes; Heat Shock Protein; Interleukin-15; Natural Killer Receptors

PMID:
26001928
PMCID:
PMC4550536
DOI:
10.1053/j.gastro.2015.05.013
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center