Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease
Open accessAbstract
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.
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Under stress or inflammatory conditions, such as in celiac disease, iIELs upregulate the expression of activating NKG2D and CD94/NKG2C receptors (which recognize MICA/B and HLA-E, respectively) while losing the expression of the inhibitory receptors CD94/NKG2A.
“Under stress or inflammatory conditions, such as in celiac disease, iIELs upregulate the expression of activating NKG2D and CD94/NKG2C receptors, (which recognize MICA/B and HLA-E, respectively) while losing the expression of the inhibitory receptors CD94/NKG2A [302, 306-308].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [307]
The Results section (page unavailable) reports that intraepithelial cytotoxic T lymphocytes in active celiac disease have high activating CD94 and NKG2D and low inhibitory NKG2A. But the paper measures activating CD94/NKG2A− receptors rather than specifically CD94/NKG2C, does not establish the stated MICA/B and HLA-E ligand pairings in its findings, and reports that epithelial stress alone increased activating receptors without loss of NKG2A. (LLM, conf=0.87)
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- Authors
- Setty, M., Discepolo, V., Abadie, V., Kamhawi, S., Mayassi, T., Kent, A., Ciszewski, C., Maglio, M., Kistner, E., Bhagat, G., Semrad, C., Kupfer, S. S., Green, P. H., Guandalini, S., Troncone, R., Murray, J. A., Turner, J. R., & Jabri, B.
- Affiliations
- University of Chicago (US)
- Université de Montréal (CA)
- University of Naples Federico II (IT)
- Columbia University Irving Medical Center (US)
- Mayo Clinic (US)
- Corresponding author
- Turner, Jerrold R.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 149
- Issue
- 3
- Pages
- 681-691.e10
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4550536
- OpenAlex
- W2100536595
- Cited by
- 119
- References
- 56
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 6 · 2023: 5 · 2022: 8 · 2021: 19 · 2020: 10 · 2019: 13 · 2018: 13 · 2017: 12 · 2016: 9 · 2015: 5 · 2014: 1
- FWCI
- 13.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000430)
- Canadian Institutes of Health Research
- National Institute of Allergy and Infectious Diseases (T32AI007090)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01_DK67180, P01DK067887, R56DK094954, R01DK098435, R01DK067180, DK42086, P30DK042086, R01DK061931)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Gastroenterology › Celiac Disease Research and Management
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Wheat and Barley Genetics and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- celiac disease, natural killer cells, heat shock proteins, IL-15, villous atrophy
- MeSH terms
- Protein Glutamine gamma Glutamyltransferase 2, Autoantibodies, Celiac Disease, Cell Communication, Epithelial Cells, Heat-Shock Proteins, Humans, Intestinal Mucosa, Intestine, Small, Italy, Phenotype, Transglutaminases, Risk Factors, Stress, Physiological, T-Lymphocytes, Cytotoxic, United States, Signal Transduction, Case-Control Studies, Molecular Chaperones, HSP70 Heat-Shock Proteins, GTP-Binding Proteins, Interleukin-15, HSP27 Heat-Shock Proteins, Adaptive Immunity
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