ARTICLES 1484 VOLUME 9 | NUMBER 12 | DECEMBER 2003 NATURE MEDICINE 1 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 7, A-1030 Vienna, Austria. 2 Department of Research and Medicine A, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. 3 Department of Pathology, University Hospital, Rämistrasse 100, CH-8091 Zurich, Switzerland. 4 The Heart & Stroke/Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada. 5 Department of Immunology, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. 6 Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistr. 27, CH-8952 Zurich-Schlieren, Switzerland. 7 Department of Medical Biophysics, University Health Network, University of Toronto, Princess Margaret Hospital, 620 University Ave, Toronto, Ontario M5G 2C1, Canada. Correspondence should be addressed to U.E. (ueriksson@uhbs.ch) or J.M.P. (josef.penninger@oeaw.ac.at). Published online 16 November 2003; doi:10.1038/nm960 Dendritic cell–induced autoimmune heart failure requires cooperation between adaptive and innate immunity Urs Eriksson 1,2 , Romeo Ricci 1 , Lukas Hunziker 2 , Michael O Kurrer 3 , Gavin Y Oudit 4 , Tania H Watts 5 , Ivo Sonderegger 6 , Kurt Bachmaier 1,7 , Manfred Kopf 6 & Josef M Penninger 1,5,7 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. Dilated cardiomyopathy is the most common cause of heart failure in young patients. The disease has been linked to autoimmune responses after infection with cardiotropic viruses, as many patients produce autoantibodies against heart proteins 1–5 . Animal models support the hypothesis that infections trigger autoimmune responses against heart tissue. Mice with a defined genetic back- ground develop prolonged myocarditis after infection with cox- sackievirus B3 (ref. 4). In the same mouse strains, immunization with heart-specific α-myosin peptides and a strong adjuvant induces CD4 + T-cell-mediated myocarditis 4,6,7 . However, the mechanisms linking microbial infections with autoimmune myocarditis and postinflammatory heart failure are still unknown. DCs are highly specialized antigen-presenting cells. Upon encountering a pathogen, DCs undergo maturation, including antigen processing, upregulation of major histocompatibility class (MHC) class II molecules, induction of costimulatory activity and migration to lymph nodes, where they prime antigen-specific T cells 8 . Because DCs also process endogenous antigens, they might trigger autoreactive T cells if activated appropriately 8–10 . In addi- tion, processing of dying cells in the absence of appropriate stimu- lation renders DCs tolerogenic for CD8 + (refs. 10,11) and CD4 + (ref. 12) T-cell-mediated responses. In the context of autoimmu- nity, transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein, under the control of the rat insulin promoter, develop autoimmune diabetes after injection of DCs constitutively expressing the immunodominant cytotoxic T-lymphocyte epitope of the viral glycoprotein 13 . CD4 + T-cell-mediated experimental autoimmune encephalomyelitis can be induced by coinjection of transgenic T cells and DCs pulsed with the corresponding self antigen 14 . In hearts of normal mice, tissue-resident DCs present endoge- nous heart-specific peptides 15 . However, it is not known whether DCs presenting endogenous self antigens might contribute to autoimmune heart disease and heart failure. Here we provide the first in vivo evidence that the concerted action of innate and adap- tive immunity on DCs triggers autoimmune heart disease, relapses and cardiomyopathy. Dendritic cells induce myocarditis Induction of autoimmunity requires the administration of autoantigens, together with strong adjuvants such as complete Freund adjuvant. Because the active ingredient of complete Freund adjuvant, inactivated mycobacteria, stimulates TLRs 16 , we decided to test whether self protein–loaded DCs can trigger autoimmunity using the previously identified heart muscle– specific α-myosin peptide MYHC-α(614–62929 17 . BALB/c (H–2 d haplotype) mice were injected with syngeneic, MYHC-α(614–62929 - pulsed CD11c + CD11b + CD80 + CD86 + CD8 – MHC class II–positive bone marrow–derived DCs activated with the TLR ligand lipopolysaccharide (LPS) and a stimulatory antibody to CD40. © 2004 Nature Publishing Group http://www.nature.com/naturemedicine