IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease.

Tytuł:: IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease.
Autorzy:: Abadie V; Department of Microbiology, Infectiology, and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. .; Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada. .; Department of Medicine, University of Chicago, Chicago, IL, USA. .
Kim SM; Department of Medicine, University of Chicago, Chicago, IL, USA.; Committee on Immunology, University of Chicago, Chicago, IL, USA.; Department of Biology, University of San Francisco, San Francisco, CA, USA.
Lejeune T; Department of Microbiology, Infectiology, and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.; Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Palanski BA; Department of Chemistry, Stanford University, Stanford, CA, USA.
Ernest JD; Department of Medicine, University of Chicago, Chicago, IL, USA.; Committee on Immunology, University of Chicago, Chicago, IL, USA.
Tastet O; Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Voisine J; Department of Medicine, University of Chicago, Chicago, IL, USA.; Committee on Immunology, University of Chicago, Chicago, IL, USA.
Discepolo V; Department of Medicine, University of Chicago, Chicago, IL, USA.
Marietta EV; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.; Department of Immunology, Mayo Clinic, Rochester, MN, USA.; Department of Dermatology, Mayo Clinic, Rochester, MN, USA.
Hawash MBF; Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.; Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
Ciszewski C; Department of Medicine, University of Chicago, Chicago, IL, USA.; Committee on Immunology, University of Chicago, Chicago, IL, USA.
Bouziat R; Department of Medicine, University of Chicago, Chicago, IL, USA.; Committee on Immunology, University of Chicago, Chicago, IL, USA.
Panigrahi K; Department of Medicine, University of Chicago, Chicago, IL, USA.
Horwath I; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
Zurenski MA; Department of Medicine, University of Chicago, Chicago, IL, USA.
Lawrence I; Department of Medicine, University of Chicago, Chicago, IL, USA.
Dumaine A; Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Yotova V; Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Grenier JC; Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Murray JA; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
Khosla C; Department of Chemistry, Stanford University, Stanford, CA, USA.; Department of Chemical Engineering, Stanford University, Stanford, CA, USA.; Stanford ChEM-H, Stanford University, Stanford, CA, USA.
Barreiro LB; Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.; Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.; Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA.
Jabri B; Department of Medicine, University of Chicago, Chicago, IL, USA. .; Committee on Immunology, University of Chicago, Chicago, IL, USA. .; Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA. .; Department of Pathology, University of Chicago, Chicago, IL, USA. .; University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA. .
Źródło:: Nature [Nature] 2020 Feb; Vol. 578 (7796), pp. 600-604. Date of Electronic Publication: 2020 Feb 12.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
MeSH Terms:: Celiac Disease/*immunology
Celiac Disease/*pathology
Glutens/*immunology
HLA-DQ Antigens/*immunology
Interleukin-15/*immunology
Animals ; CD4-Positive T-Lymphocytes/immunology ; Female ; HLA-DQ Antigens/genetics ; Humans ; Interferon-gamma/immunology ; Interleukin-15/genetics ; Male ; Mice ; Mice, Transgenic ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism
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Grant Information:: T32 DK007074 United States DK NIDDK NIH HHS; T32 AI007090 United States AI NIAID NIH HHS; R01 DK100619 United States DK NIDDK NIH HHS; R01 DK063158 United States DK NIDDK NIH HHS; R01 DK067180 United States DK NIDDK NIH HHS; P30 DK042086 United States DK NIDDK NIH HHS
Substance Nomenclature:: 0 (HLA-DQ Antigens)
0 (HLA-DQ8 antigen)
0 (IL15 protein, human)
0 (Interleukin-15)
0 (Microfilament Proteins)
0 (villin)
8002-80-0 (Glutens)
82115-62-6 (Interferon-gamma)
Entry Date(s):: Date Created: 20200214 Date Completed: 20200403 Latest Revision: 20210223
Update Code:: 20240105
PubMed Central ID:: PMC7047598
DOI:: 10.1038/s41586-020-2003-8
PMID:: 32051586
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Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes 1,2 . The need to develop non-dietary treatments is now widely recognized 3 , but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease 4 , the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4 + T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.

Comment in: Nat Rev Gastroenterol Hepatol. 2020 Apr;17(4):194-195. (PMID: 32123376)

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