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

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  • Additional Information
    • Source:
      Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE
    • Publication Information:
      Publication: Philadelphia, PA : W.B. Saunders
      Original Publication: Baltimore.
    • Subject Terms:
      Adaptive Immunity* ; Cell Communication* ; Stress, Physiological*; Celiac Disease/*immunology ; Epithelial Cells/*immunology ; Intestinal Mucosa/*immunology ; Intestine, Small/*immunology ; T-Lymphocytes, Cytotoxic/*immunology; 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
    • 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.
      (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
    • Comments:
      Comment in: Nat Rev Gastroenterol Hepatol. 2015 Sep;12(9):491-2. (PMID: 26194946)
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    • Grant Information:
      UL1 TR000430 United States TR NCATS NIH HHS; R56 DK094954 United States DK NIDDK NIH HHS; Canada CAPMC CIHR; R01DK098435 United States DK NIDDK NIH HHS; T32 AI007090 United States AI NIAID NIH HHS; R01DK67180 United States DK NIDDK NIH HHS; R01 DK098435 United States DK NIDDK NIH HHS; P01 DK067887 United States DK NIDDK NIH HHS; R01 DK067180 United States DK NIDDK NIH HHS; P30 DK042086 United States DK NIDDK NIH HHS; R01 DK061931 United States DK NIDDK NIH HHS; DK42086 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: Cytotoxic Intraepithelial Lymphocytes; Heat Shock Protein; Interleukin-15; Natural Killer Receptors
    • Accession Number:
      0 (Autoantibodies)
      0 (HSP27 Heat-Shock Proteins)
      0 (HSP70 Heat-Shock Proteins)
      0 (HSPB1 protein, human)
      0 (Heat-Shock Proteins)
      0 (IL15 protein, human)
      0 (Interleukin-15)
      0 (Molecular Chaperones)
      0 (TGM2 protein, human)
      EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2)
      EC 2.3.2.13 (Transglutaminases)
      EC 3.6.1.- (GTP-Binding Proteins)
    • Publication Date:
      Date Created: 20150524 Date Completed: 20151109 Latest Revision: 20220512
    • Publication Date:
      20221213
    • Accession Number:
      PMC4550536
    • Accession Number:
      10.1053/j.gastro.2015.05.013
    • Accession Number:
      26001928