Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity.
Genetic susceptibility and autoimmunity triggered by microbial infections are factors implicated in the pathogenesis of dilated cardiomyopathy, the most common cause of heart failure in young patients. Here we show that dendritic cells (DCs) loaded with a heart-specific self peptide induce CD4+ T-cell-mediated myocarditis in nontransgenic mice. Toll-like receptor (TLR) stimulation, in concert with CD40 triggering of self peptide-loaded dendritic cells, was shown to be required for disease induction. After resolution of acute myocarditis, DC-immunized mice developed heart failure, and TLR stimulation of these mice resulted in relapse of inflammatory infiltrates. Injection of damaged, syngeneic cardiomyocytes also induced myocarditis in mice if TLRs were activated in vivo. DC-induced myocarditis provides a unifying theory as to how tissue damage and activation of TLRs during infection can induce autoimmunity, relapses and cardiomyopathy.
Eriksson
Urs
U
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 7, A-1030 Vienna, Austria. ueriksson@uhbs.ch
Ricci
Romeo
R
Hunziker
Lukas
L
Kurrer
Michael O
MO
Oudit
Gavin Y
GY
Watts
Tania H
TH
Sonderegger
Ivo
I
Bachmaier
Kurt
K
Kopf
Manfred
M
Penninger
Josef M
JM
D000222:Adaptation, Physiological; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D018448:Models, Immunological; D010446:Peptide Fragments / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism; D051193:Toll-Like Receptors; D024723:Ventricular Myosins / Q000276:immunology
D001324:Autoantigens; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D024723:Ventricular Myosins