title: Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes.
abstract: Posttranslational modifications of self-proteins play a substantial role in the initiation or propagation of the autoimmune attack in several autoimmune diseases, but their contribution to type 1 diabetes is only recently emerging. In the current study, we demonstrate that inflammatory stress, induced by the cytokines interleukin-1β and interferon-γ, leads to citrullination of GRP78 in β-cells. This is coupled with translocation of this endoplasmic reticulum chaperone to the β-cell plasma membrane and subsequent secretion. Importantly, expression and activity of peptidylarginine deiminase 2, one of the five enzymes responsible for citrullination and a candidate gene for type 1 diabetes in mice, is increased in islets from diabetes-prone nonobese diabetic (NOD) mice. Finally, (pre)diabetic NOD mice have autoantibodies and effector T cells that react against citrullinated GRP78, indicating that inflammation-induced citrullination of GRP78 in β-cells generates a novel autoantigen in type 1 diabetes, opening new avenues for biomarker development and therapeutic intervention.
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Rondas
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Inne
authors.initials: I
authors.lastname: Crèvecoeur
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Wannes
authors.initials: W
authors.lastname: D'Hertog
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Gabriela Bomfim
authors.initials: GB
authors.lastname: Ferreira
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Staes
authors.affiliation: Laboratory for Cell Death Research and Therapy, KU Leuven, Leuven, Belgium.
authors.forename: Abhishek D
authors.initials: AD
authors.lastname: Garg
authors.affiliation: Laboratory of Experimental Medicine and Université Libre de Bruxelles Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: Laboratory for Cell Death Research and Therapy, KU Leuven, Leuven, Belgium.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium lut.overbergh@med.kuleuven.be.
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D002956:Citrulline; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000276:immunology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D053583:Interleukin-1beta; D002956:Citrulline; D007371:Interferon-gamma