title: Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois.
authors.forename: Mala
authors.initials: M
authors.lastname: Setty
authors.affiliation: 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.
authors.forename: Valentina
authors.initials: V
authors.lastname: Discepolo
authors.affiliation: Sainte-Justine Hospital Research Center, Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Abadie
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kamhawi
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Toufic
authors.initials: T
authors.lastname: Mayassi
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kent
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Cezary
authors.initials: C
authors.lastname: Ciszewski
authors.affiliation: European Laboratory for the Investigation of Food-Induced Disorders, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Maglio
authors.affiliation: Department of Health Studies, University of Chicago, Chicago, Illinois.
authors.forename: Emily
authors.initials: E
authors.lastname: Kistner
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Carol
authors.initials: C
authors.lastname: Semrad
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Kupfer
authors.affiliation: Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, New York.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Green
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guandalini
authors.affiliation: European Laboratory for the Investigation of Food-Induced Disorders, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Troncone
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois; Department of Pathology, University of Chicago, Chicago, Illinois. Electronic address: jturner@bsd.uchicago.edu.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois; Department of Medicine, University of Chicago, Chicago, Illinois. Electronic address: bjabri@bsd.uchicago.edu.
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
mesh_terms: D056704:Adaptive Immunity; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D002446:Celiac Disease / Q000097:blood / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D019204:GTP-Binding Proteins / Q000276:immunology; D055551:HSP27 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D007421:Intestine, Small / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D007558:Italy; D018832:Molecular Chaperones; D010641:Phenotype; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012307:Risk Factors; D015398:Signal Transduction; D013312:Stress, Physiological; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D011503:Transglutaminases / Q000276:immunology; D014481:United States
chemical_list: D001323:Autoantibodies; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C569274:IL15 protein, human; D019409:Interleukin-15; D018832:Molecular Chaperones; C000717608:TGM2 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Cytotoxic Intraepithelial Lymphocytes; Heat Shock Protein; Interleukin-15; Natural Killer Receptors