title: Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis.
abstract: Experimental autoimmune myocarditis (EAM) is a CD4(+) T-cell-mediated model of human inflammatory dilated cardiomyopathies. Heart-specific CD4(+) T-cell activation is dependent on autoantigens presented by MHC class II (MHCII) molecules expressed on professional APCs. In this study, we addressed the role of inflammation-induced MHCII expression by cardiac nonhematopoietic cells on EAM development. EAM was induced in susceptible mice lacking inducible expression of MHCII molecules on all nonhematopoietic cells (pIV-/- K14 class II transactivator (CIITA) transgenic (Tg) mice) by immunization with α-myosin heavy chain peptide in CFA. Lack of inducible nonhematopoietic MHCII expression in pIV-/- K14 CIITA Tg mice conferred EAM resistance. In contrast, cardiac pathology was induced in WT and heterozygous mice, and correlated with elevated cardiac endothelial MHCII expression. Control mice with myocarditis displayed an increase in infiltrating CD4(+) T cells and in expression of IFN-γ, which is the major driver of nonhematopoietic MHCII expression. Mechanistically, IFN-γ neutralization in WT mice shortly before disease onset resulted in reduced cardiac MHCII expression and pathology. These findings reveal a previously overlooked contribution of IFN-γ to induce endothelial MHCII expression in the heart and to progress cardiac pathology during myocarditis.
authors.affiliation: Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thelemann
authors.affiliation: Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Haller
authors.affiliation: Division of Cardioimmunology, Centre of Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Blyszczuk
authors.affiliation: Research of Systemic Autoimmune Diseases, Division of Rheumatology, University Hospital Zürich, Schlieren, Switzerland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kania
authors.affiliation: Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland.
authors.forename: Muriel
authors.initials: M
authors.lastname: Rosa
authors.affiliation: Division of Cardioimmunology, Centre of Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.affiliation: Institute of Pathology, CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rotman
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.affiliation: Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
mesh_terms: D000818:Animals; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes; D004195:Disease Models, Animal; D004727:Endothelium / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology*; D007249:Inflammation; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology*; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics
chemical_list: D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D007371:Interferon-gamma
keywords: CD4+ T cells; Endothelial antigen presentation; Experimental autoimmune myocarditis (EAM); Interferon-γ; MHC class II