This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 113/2/258    most recent CIRCULATIONAHA.105.564294v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marty, R. R. Articles by Eriksson, U. Search for Related Content PubMed PubMed Citation Articles by Marty, R. R. Articles by Eriksson, U. Related Collections Other myocardial biology Congestive Animal models of human disease

(Circulation. 2006;113:258-265.)
© 2006 American Heart Association, Inc.

Heart Failure

MyD88 Signaling Controls Autoimmune Myocarditis Induction

René R. Marty, MSc; Stephan Dirnhofer, MD; Nora Mauermann, MSc; Sacha Schweikert, MD; Shizuo Akira, MD; Lukas Hunziker, MD; Josef M. Penninger, MD; Urs Eriksson, MD

From the Division of Experimental Critical Care Medicine, Department of Research (R.R.M., N.M., S.S., U.E.), Medicine A, Department of Internal Medicine (L.H., U.E.), and Institute of Pathology (S.D., S.S.), University Hospital, Basel, Switzerland; Department of Host Defence (S.A.), Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and IMBA (J.M.P.), Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

Correspondence to Urs Eriksson, MD, Medicine A, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail ueriksson{at}uhbs.ch

Received May 23, 2005; revision received October 27, 2005; accepted November 11, 2005.

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.

Methods and Results— In contrast to control littermates, MyD88^–/– mice were protected from myocarditis after immunization with -myosin heavy chain–derived peptide (MyHC-) 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-. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-–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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				P. Zhang, C. J. Cox, K. M. Alvarez, and M. W. Cunningham Cutting Edge: Cardiac Myosin Activates Innate Immune Responses through TLRs J. Immunol., July 1, 2009; 183(1): 27 - 31. [Abstract] [Full Text] [PDF]

				A. Valaperti, R. R. Marty, G. Kania, D. Germano, N. Mauermann, S. Dirnhofer, B. Leimenstoll, P. Blyszczuk, C. Dong, C. Mueller, et al. CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis J. Immunol., February 15, 2008; 180(4): 2686 - 2695. [Abstract] [Full Text] [PDF]