MyD88 signaling controls autoimmune myocarditis induction.
BACKGROUND
Experimental autoimmune myocarditis (EAM) is a CD4+ T-cell-mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known.


RESULTS
In contrast to control littermates, MyD88(-/-) mice were protected from myocarditis after immunization with alpha-myosin heavy chain-derived peptide (MyHC-alpha) and complete Freund's adjuvant. Disease resistance of MyD88(-/-) mice resulted from impaired expansion of heart-specific CD4+ T cells after immunization. Intrinsic defects of MyD88(-/-) CD4+ T cells were excluded. In contrast, MyD88(-/-) but not MyD88(+/+) primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4+ T cells. This defect mainly resulted from the inability of MyD88(-/-) DCs to release tumor necrosis factor-alpha. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-alpha-loaded MyD88(+/+) DCs that fully restored T-cell expansion and myocarditis in MyD88(-/-) mice.


CONCLUSIONS
Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.
Marty
René R
RR
Division of Experimental Critical Care Medicine, Department of Research, University Hospital, Basel, Switzerland.
Dirnhofer
Stephan
S
Mauermann
Nora
N
Schweikert
Sacha
S
Akira
Shizuo
S
Hunziker
Lukas
L
Penninger
Josef M
JM
Eriksson
Urs
U
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D009205:Myocarditis / Q000209:etiology* / Q000276:immunology; D018995:Myosin Heavy Chains / Q000008:administration & dosage / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D024723:Ventricular Myosins / Q000008:administration & dosage / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains