(Circulation. 1997;95:655-661.)
© 1997 American Heart Association, Inc.
Articles |
Low-Molecular-Weight Tumor Necrosis Factor Receptor p55 Controls Induction of Autoimmune Heart Disease
the Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Canada; the Institute for Medical Microbiology and Hygiene, Technical University, Munich, Germany (K.P.); and the Department of Pediatrics, University of Innsbruck, Austria (C.P., N.N.).
Correspondence to Josef Penninger, Amgen Institute/Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Ave, Toronto, Ontario, M5G 2C1 Canada. E-mail jpenning@amgen.com.
Background Tumor necrosis factor-
(TNF-) is involved in the pathogenesis of myocarditis and can bind to either tumor necrosis factor receptor (TNF-R) p55 or TNF-Rp75. However, it is not known which TNF-R mediates the specific functions of TNF in disease. To determine the role of the TNF/TNF-R system in chronic heart disease, we used a murine model of cardiac myosin–induced myocarditis that closely resembles the chronic stages of virus-induced myocarditis in humans.
Methods and Results Mice lacking TNF-Rp55 expression after targeted disruption of the TNF-Rp55 gene were backcrossed into a genetic background susceptible to the induction of myocarditis with cardiac myosin. Here, we demonstrate that TNF-Rp55 gene–deficient mice did not develop any inflammatory infiltration into the heart after autoantigen injection, whereas control littermates showed autoimmune myocarditis at high prevalence and severity. Despite the absence of autoimmune heart disease, TNF-Rp55-/- mice produced cardiac myosin–specific IgG autoantibodies, indicating that activation of autoaggressive T and B lymphocytes had occurred. However, heart interstitial cells failed to express major histocompatibility complex (MHC) class II molecules in TNF-Rp55-/- animals, and adoptive transfer of autoreactive T cells resulted in heart disease only in TNF-Rp55+/+ but not in TNF-Rp55-/- littermates.
Conclusions Cardiac myosin–induced myocarditis is dependent on autoaggressive T cells and on autoantigen presentation in association with MHC class II molecules within the heart. Thus, lack of TNF-Rp55 expression could interfere with either lymphocyte activation or target organ susceptibility. The data presented here show that the TNF-Rp55 is a key regulator for the induction of autoimmune heart disease by its controlling target organ susceptibility.
Key Words: myocarditis • molecular biology • signal transduction • genetics
This article has been cited by other articles:
 |
|
 |
|
  J. S. Hui-Yuen, T. T. Duong, and R. S. M. Yeung TNF-{alpha} Is Necessary for Induction of Coronary Artery Inflammation and Aneurysm Formation in an Animal Model of Kawasaki Disease J. Immunol., May 15, 2006; 176(10): 6294 - 6301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Petkova-Kirova, E. Gursoy, H. Mehdi, C. F. McTiernan, B. London, and G. Salama Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-{alpha} Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2098 - H2107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Marty, S. Dirnhofer, N. Mauermann, S. Schweikert, S. Akira, L. Hunziker, J. M. Penninger, and U. Eriksson MyD88 Signaling Controls Autoimmune Myocarditis Induction Circulation, January 17, 2006; 113(2): 258 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Khoynezhad, Z. Jalali, and A. J. Tortolani Apoptosis: Pathophysiology and therapeutic implications for the cardiac surgeon Ann. Thorac. Surg., September 1, 2004; 78(3): 1109 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higuchi, C. F. McTiernan, C. B. Frye, B. S. McGowan, T. O. Chan, and A. M. Feldman Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-{alpha}-Induced Cardiomyopathy Circulation, April 20, 2004; 109(15): 1892 - 1897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Eriksson, M. O. Kurrer, I. Sonderegger, G. Iezzi, A. Tafuri, L. Hunziker, S. Suzuki, K. Bachmaier, R. M. Bingisser, J. M. Penninger, et al. Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis J. Exp. Med., February 3, 2003; 197(3): 323 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Eriksson, M. O. Kurrer, N. Schmitz, S. C. Marsch, A. Fontana, H.-P. Eugster, and M. Kopf Interleukin-6-Deficient Mice Resist Development of Autoimmune Myocarditis Associated With Impaired Upregulation of Complement C3 Circulation, January 21, 2003; 107(2): 320 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Afanasyeva and N.R. Rose Immune mediators in inflammatory heart disease: insights from a mouse model Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I31 - I36. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Afanasyeva and N. R. Rose Cardiomyopathy Is Linked to Complement Activation Am. J. Pathol., August 1, 2002; 161(2): 351 - 357. [Full Text] [PDF]
|
|
|
|
 |
|
 P. P. Liu, J. Le, and M. Nian Nuclear Factor-{kappa}B Decoy: Infiltrating the Heart of the Matter in Inflammatory Heart Disease Circ. Res., November 9, 2001; 89(10): 850 - 852. [Full Text] [PDF]
|
|
|
|
|
|
P. P. Liu and J. W. Mason Advances in the Understanding of Myocarditis Circulation, August 28, 2001; 104(9): 1076 - 1082. [Full Text] [PDF]
|
|
|
|
|
|
M. W. Cunningham Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis Am. J. Pathol., July 1, 2001; 159(1): 5 - 12. [Full Text] [PDF]
|
|
|
|
|
|
M. Afanasyeva, Y. Wang, Z. Kaya, S. Park, M. J. Zilliox, B. H. Schofield, S. L. Hill, and N. R. Rose Experimental Autoimmune Myocarditis in A/J mice Is an Interleukin-4-Dependent Disease with a Th2 Phenotype Am. J. Pathol., July 1, 2001; 159(1): 193 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kadokami, C. F. McTiernan, T. Kubota, C. S. Frye, G. S. Bounoutas, P. D. Robbins, S. C. Watkins, and A. M. Feldman Effects of soluble TNF receptor treatment on lipopolysaccharide-induced myocardial cytokine expression Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2281 - H2291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wada, K. Saito, T. Kanda, I. Kobayashi, H. Fujii, S. Fujigaki, N. Maekawa, H. Takatsu, H. Fujiwara, K. Sekikawa, et al. Tumor Necrosis Factor-{{alpha}} (TNF-{{alpha}}) Plays a Protective Role in Acute Viral Myocarditis in Mice : A Study Using Mice Lacking TNF-{{alpha}} Circulation, February 6, 2001; 103(5): 743 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Eriksson, M. O. Kurrer, R. Bingisser, H. P. Eugster, P. Saremaslani, F. Follath, S. Marsch, and U. Widmer Lethal Autoimmune Myocarditis in Interferon-{{gamma}} Receptor-Deficient Mice : Enhanced Disease Severity by Impaired Inducible Nitric Oxide Synthase Induction Circulation, January 2, 2001; 103(1): 18 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, M. Afanasyeva, S. L. Hill, Z. Kaya, and N. R. Rose Nasal administration of cardiac myosin suppresses autoimmune myocarditis in mice J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1992 - 1999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Probert, H.-P. Eugster, K. Akassoglou, J. Bauer, K. Frei, H. Lassmann, and A. Fontana TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease Brain, October 1, 2000; 123(10): 2005 - 2019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Feldman, A. Combes, D. Wagner, T. Kadakomi, T. Kubota, Y. You Li, and C. McTiernan The role of tumor necrosis factor in the pathophysiology of heart failure J. Am. Coll. Cardiol., March 1, 2000; 35(3): 537 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Bachmaier, N. Neu, R. S. M. Yeung, T. W. Mak, P. Liu, and J. M. Penninger Generation of Humanized Mice Susceptible to Peptide-Induced Inflammatory Heart Disease Circulation, April 13, 1999; 99(14): 1885 - 1891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Nishina, C Vaz, P Billia, M Nghiem, T Sasaki, J. De la Pompa, K Furlonger, C Paige, C Hui, K. Fischer, et al. Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4 Development, January 2, 1999; 126(3): 505 - 516. [Abstract] [PDF]
|
|
|
|
|
|
A. Haunstetter and S. Izumo Apoptosis : Basic Mechanisms and Implications for Cardiovascular Disease Circ. Res., June 15, 1998; 82(11): 1111 - 1129. [Full Text] [PDF]
|
|
|
|
|
|
P. Libby and R. N. Mitchell Cytokines Score a Knockout: Harnessing Gene Targeting to Gain Insight Into the Pathogenesis of Myocarditis Circulation, February 4, 1997; 95(3): 551 - 552. [Full Text]
|
|
|
|
 |
|
 D. Hudrisier, J. Riond, O. Burlet-Schiltz, M. G. von Herrath, H. Lewicki, B. Monsarrat, M. B. A. Oldstone, and J. E. Gairin Structural and Functional Identification of Major Histocompatibility Complex Class I-restricted Self-peptides as Naturally Occurring Molecular Mimics of Viral Antigens. POSSIBLE ROLE IN CD8+ T CELL-MEDIATED, VIRUS-INDUCED AUTOIMMUNE DISEASE J. Biol. Chem., May 25, 2001; 276(22): 19396 - 19403. [Abstract] [Full Text] [PDF]
|
|