Mala Setty1, Valentina Discepolo2, Valérie Abadie3, Sarah Kamhawi4, Toufic Mayassi4, Andrew Kent4, Cezary Ciszewski4, Maria Maglio5, Emily Kistner6, Govind Bhagat7, Carol Semrad4, Sonia S Kupfer4, Peter H Green8, Stefano Guandalini1, Riccardo Troncone5, Joseph A Murray9, Jerrold R Turner10, Bana Jabri11. 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.
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.
Authors: A Tosco; R Auricchio; R Aitoro; D Ponticelli; M Primario; E Miele; V Rotondi Aufiero; V Discepolo; L Greco; R Troncone; M Maglio Journal: Clin Exp Immunol Date: 2014-09 Impact factor: 4.330
Authors: B Jabri; N P de Serre; C Cellier; K Evans; C Gache; C Carvalho; J F Mougenot; M Allez; R Jian; P Desreumaux; J F Colombel; C Matuchansky; H Cugnenc; M Lopez-Botet; E Vivier; A Moretta; A I Roberts; E C Ebert; D Guy-Grand; N Brousse; J Schmitz; N Cerf-Bensussan Journal: Gastroenterology Date: 2000-05 Impact factor: 22.682
Authors: Marlies Meisel; Toufic Mayassi; Hannah Fehlner-Peach; Jason C Koval; Sarah L O'Brien; Reinhard Hinterleitner; Kathryn Lesko; Sangman Kim; Romain Bouziat; Li Chen; Christopher R Weber; Sarkis K Mazmanian; Bana Jabri; Dionysios A Antonopoulos Journal: ISME J Date: 2016-09-20 Impact factor: 10.302