Clinical Research in Cardiology

, Volume 96, Issue 7, pp 469–480 | Cite as

Autoimmunological features in inflammatory cardiomyopathy

  • Angela Kallwellis-Opara
  • Andrea Dörner
  • Wolfgang-Christian Poller
  • Michel Noutsias
  • Uwe Kühl
  • Heinz-Peter Schultheiss
  • Mathias PauschingerEmail author


During recent years, increasing evidence has been obtianed that cellular as well as humoral autoimmunity is involved in the pathogenesis of dilated cardiomyopathy (DCM). The immune system is generally activated by viral infections with the objective of virus elimination from the myocardium. However, a relevant number of patients demonstrate viral persistence and/or chronic inflammation in the myocardium. This chronic myocardial inflammation, defined by chronic inflammation, is termed “inflammatory cardiomyopathy” according to the WHO classification of cardiomyopathies. Chronic inflammation is frequently followed by the development of autoimmunity. A breakdown in the control mechanisms protecting against autoimmune reactions by both presentation of normally not accessible self-antigens and bystander- activation, induced by the pathogen, leads to the formation of autoreactive antibodies and T cells. The auto-reactive antibodies interact directly with heart tissue resulting in altered signal transduction or complement activation, whereas the T cell-mediated mechanisms include direct attack by cytotoxic T cells or indirect effects of cytotoxic cytokines released by stimulated T cells or macrophages.

Key words

inflammatory cardiomyopathy autoimmunity cardiac antigens 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Afanasyeva M, Georgakopoulos D, Belardi DF, Bedja D, Fairweather D, Wang Y, Kaya Z, Gabrielson KL, Rodriguez ER, Caturegli P, Kass DA, Rose NR (2005) Impaired up-regulation of CD25 on CD4+ T cells in IFNgamma knockout mice is associated with progression of myocarditis to heart failure. Proc Natl Acad Sci USA 102:180–185PubMedCrossRefGoogle Scholar
  2. 2.
    Afanasyeva M, Wang Y, Kaya Z, Park S, Zilliox MJ, Schofield BH, Hill SL, Rose NR (2001) Experimental autoimmune myocarditis in A/J mice is an interleukin-4-dependent disease with a Th2 phenotype. Am J Pathol 159:193–203PubMedGoogle Scholar
  3. 3.
    Afanasyeva M, Wang Y, Kaya Z, Stafford EA, Dohmen KM, Sadighi Akha AA, Rose NR (2001) Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferongamma- independent pathway. Circulation 104:3145–3151PubMedGoogle Scholar
  4. 4.
    Albert LJ, Inman RD (1999) Molecular mimicry and autoimmunity. N Engl J Med 341:2068–2074PubMedCrossRefGoogle Scholar
  5. 5.
    Alter P, Maisch B (2004) Escape from cardiomyocyte apoptosis by enterovirus persistence due to elevated soluble Fas-receptors. Z Kardiol 93(7):524–532PubMedCrossRefGoogle Scholar
  6. 6.
    Alvarez FL, Neu N, Rose NR, Craig SW, Beisel KW (1987) Heart-specific autoantibodies induced by Coxsackievirus B3: identification of heart autoantigens. Clin Immunol Immunopathol 43:129–139PubMedCrossRefGoogle Scholar
  7. 7.
    Ansari AA, Neckelmann N, Villinger F, Leung P, Danner DJ, Brar SS, Zhao S, Gravanis MB, Mayne A, Gershwin ME (1994) Epitope mapping of the branched chain alpha-ketoacid dehydrogenase dihydrolipoyl transacylase (BCKD-E2) protein that reacts with sera from patients with idiopathic dilated cardiomyopathy. J Immunol 153:4754–4765PubMedGoogle Scholar
  8. 8.
    Ansari AA, Wang YC, Danner DJ, Gravanis MB, Mayne A, Neckelmann N, Sell KW, Herskowitz A (1991) Abnormal expression of histocompatibility and mitochondrial antigens by cardiac tissue from patients with myocarditis and dilated cardiomyopathy. Am J Pathol 139:337–354PubMedGoogle Scholar
  9. 9.
    Baba A, Yoshikawa T, Mitamura H, Akaishi M, Ogawa S (2002) [Autoantibodies against sarcolemmal Na-KATPase in patients with dilated cardiomyopathy: autoimmune basis for ventricular arrhythmias in patients with congestive heart failure]. J Cardiol 39:50–51PubMedGoogle Scholar
  10. 10.
    Banchereau J (1995) Converging and diverging properties of human interleukin- 4 and interleukin-10. Behring Inst Mitt 96:58–77PubMedGoogle Scholar
  11. 11.
    Bartlett EJ, Lenzo JC, Sivamoorthy S, Mansfield JP, Cull VS, James CM (2004) Type I IFN-beta gene therapy suppresses cardiac CD8+ T-cell infiltration during autoimmune myocarditis. Immunol Cell Biol 82:119–126PubMedCrossRefGoogle Scholar
  12. 12.
    Beisel KW, Srinivasappa J, Prabhakar BS (1991) Identification of a putative shared epitope between Coxsackie virus B4 and alpha cardiac myosin heavy chain. Clin Exp Immunol 86:49–55PubMedCrossRefGoogle Scholar
  13. 13.
    Biron CA (1999) Initial and innate responses to viral infections–pattern setting in immunity or disease. Curr Opin Microbiol 2:374–381PubMedCrossRefGoogle Scholar
  14. 14.
    Borda E, Pascual J, Cossio P, De L, V, Arana R, Sterin-Borda L (1984) A circulating IgG in Chagas’ disease which binds to beta-adrenoceptors of myocardium and modulates their activity. Clin Exp Immunol 57:679–686PubMedGoogle Scholar
  15. 15.
    Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL (2001) Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 103:1044–1047PubMedGoogle Scholar
  16. 16.
    Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, Thompson M, Giroir B (1998) Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 97:1375–1381PubMedGoogle Scholar
  17. 17.
    Caforio AL, Goldman JH, Haven AJ, Baig KM, McKenna WJ (1996) Evidence for autoimmunity to myosin and other heart-specific autoantigens in patients with dilated cardiomyopathy and their relatives. Int J Cardiol 54:157–163PubMedCrossRefGoogle Scholar
  18. 18.
    Caforio AL, Grazzini M, Mann JM, Keeling PJ, Bottazzo GF, McKenna WJ, Schiaffino S (1992) Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation 85:1734–1742PubMedGoogle Scholar
  19. 19.
    Caforio AL, Mahon NJ, McKenna WJ (2001) Cardiac autoantibodies to myosin and other heart-specific autoantigens in myocarditis and dilated cardiomyopathy. Autoimmunity 34:199–204PubMedGoogle Scholar
  20. 20.
    Caforio AL, Mahon NJ, Tona F, McKenna WJ (2002) Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance. Eur J Heart Fail 4:411–417PubMedCrossRefGoogle Scholar
  21. 21.
    Caforio AL, Stewart JT, Bonifacio E, Burke M, Davies MJ, McKenna WJ, Bottazzo GF (1990) Inappropriate major histocompatibility complex expression on cardiac tissue in dilated cardiomyopathy. Relevance for autoimmunity? J Autoimmun 3:187–200PubMedCrossRefGoogle Scholar
  22. 22.
    Caspi RR (1998) IL-12 in autoimmunity. Clin Immunol Immunopathol 88:4–13PubMedCrossRefGoogle Scholar
  23. 23.
    Chandrasekar B, Melby PC, Troyer DA, Colston JT, Freeman GL (1998) Temporal expression of pro-inflammatory cytokines and inducible nitric oxide synthase in experimental acute Chagasic cardiomyopathy. Am J Pathol 152:925–934PubMedGoogle Scholar
  24. 24.
    Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107:3133–3140PubMedCrossRefGoogle Scholar
  25. 25.
    Conrad B (2003) Potential mechanisms of interferon-alpha induced autoimmunity. Autoimmunity 36:519– 523PubMedCrossRefGoogle Scholar
  26. 26.
    Crispin JC, Vargas MI, cocer-Varela J (2004) Immunoregulatory T cells in autoimmunity. Autoimmun Rev 3:45–51PubMedCrossRefGoogle Scholar
  27. 27.
    Cunningham MW (2001) Cardiac myosin and the TH1/TH2 paradigm in autoimmune myocarditis. Am J Pathol 159:5–12PubMedGoogle Scholar
  28. 28.
    Cunningham MW (2004) T cell mimicry in inflammatory heart disease. Mol Immunol 40:1121–1127PubMedCrossRefGoogle Scholar
  29. 29.
    Cunningham MW, Antone SM, Gulizia JM, McManus BM, Fischetti VA, Gauntt CJ (1992) Cytotoxic and viral neutralizing antibodies crossreact with streptococcal M protein, enteroviruses, and human cardiac myosin. Proc Natl Acad Sci USA 89:1320–1324PubMedCrossRefGoogle Scholar
  30. 30.
    Curfs JH, Meis JF, Hoogkamp-Korstanje JA (1997) A primer on cytokines: sources, receptors, effects, and inducers. Clinical Microbiology Reviews 10:742–780PubMedGoogle Scholar
  31. 31.
    Das SK, Cassidy JT, Petty RE (1972) Antibodies against heart muscle and nuclear constituents in cardiomyopathy. Am Heart J 83:159–166PubMedCrossRefGoogle Scholar
  32. 32.
    de Waal MR (1997) The role of type I interferons in the differentiation and function of Th1 and Th2 cells. Semin Oncol 24:S9Google Scholar
  33. 33.
    Dell A, Antone SM, Gauntt CJ, Crossley CA, Clark WA, Cunningham MW (1991) Autoimmune determinants of rheumatic carditis: localization of epitopes in human cardiac myosin. Eur Heart J 12 Suppl D:158–162PubMedGoogle Scholar
  34. 34.
    Deonarain R, Cerullo D, Fuse K, Liu PP, Fish EN (2004) Protective Role for Interferon-{beta} in Coxsackievirus B3 Infection. Circulation 110:3540–3543PubMedCrossRefGoogle Scholar
  35. 35.
    Deswal A, Bozkurt B, Seta Y, Parilti- Eiswirth S, Hayes FA, Blosch C, Mann DL (1999) Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 99:3224–3226PubMedGoogle Scholar
  36. 36.
    Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL (2001) Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103:2055–2059PubMedGoogle Scholar
  37. 37.
    Dorffel WV, Felix SB, Wallukat G, Brehme S, Bestvater K, Hofmann T, Kleber FX, Baumann G, Reinke P (1997) Short-term hemodynamic effects of immunoadsorption in dilated cardiomyopathy. Circulation 95:1994–1997PubMedGoogle Scholar
  38. 38.
    Dwyer JM (1992) Manipulating the immune system with immune globulin. N Engl J Med 326:107–116PubMedCrossRefGoogle Scholar
  39. 39.
    Eriksson U, Kurrer MO, Bingisser R, Eugster HP, Saremaslani P, Follath F, Marsch S, Widmer U (2001) Lethal autoimmune myocarditis in interferongamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction. Circulation 103:18–21PubMedGoogle Scholar
  40. 40.
    Eriksson U, Kurrer MO, Sebald W, Brombacher F, Kopf M (2001) Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma. J Immunol 167:5464–5469PubMedGoogle Scholar
  41. 41.
    Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, Gatewood SJ, Njoku DB, Rose NR (2004) Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin- 1 beta, and interleukin-4 in the heart. Am J Pathol 165:1883–1894PubMedGoogle Scholar
  42. 42.
    Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, Steele RA, Gatewood SJ, Rose NR (2005) IL- 12 protects against coxsackievirus B3induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. J Immunol 174:261–269PubMedGoogle Scholar
  43. 43.
    Felix SB, Staudt A, Dorffel WV, Stangl V, Merkel K, Pohl M, Docke WD, Morgera S, Neumayer HH, Wernecke KD, Wallukat G, Stangl K, Baumann G (2000) Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: threemonth results from a randomized study. J Am Coll Cardiol 35:1590–1598PubMedCrossRefGoogle Scholar
  44. 44.
    Felix SB, Staudt A, Friedrich GB (2001) Improvement of cardiac function after immunoadsorption in patients with dilated cardiomyopathy. Autoimmunity 34:211–215PubMedGoogle Scholar
  45. 45.
    Felix SB, Staudt A, Landsberger M, Grosse Y, Stangl V, Spielhagen T, Wallukat G, Wernecke KD, Baumann G, Stangl K (2002) Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. J Am Coll Cardiol 39:646–652PubMedCrossRefGoogle Scholar
  46. 46.
    Ferrari R, Bachetti T, Confortini R, Opasich C, Febo O, Corti A, Cassani G, Visioli O (1995) Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 92:1479–1486PubMedGoogle Scholar
  47. 47.
    Fischetti VA (1991) Streptococcal M protein. Sci Am 264:58–65PubMedCrossRefGoogle Scholar
  48. 48.
    Fournie GJ, Mas M, Cautain B, Savignac M, Subra JF, Pelletier L, Saoudi A, Lagrange D, Calise M, Druet P (2001) Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals. J Autoimmun 16:319–326PubMedCrossRefGoogle Scholar
  49. 49.
    Fu LX, Magnusson Y, Bergh CH, Liljeqvist JA, Waagstein F, Hjalmarson A, Hoebeke J (1993) Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor- 2 in patients with idiopathic dilated cardiomyopathy. J Clin Invest 91:1964–1968PubMedGoogle Scholar
  50. 50.
    Fu ML, Hoebeke J, Matsui S, Matoba M, Magnusson Y, Hedner T, Herlitz H, Hjalmarson A (1994) Autoantibodies against cardiac G-proteincoupled receptors define different populations with cardiomyopathies but not with hypertension. Clin Immunol Immunopathol 72:15–20PubMedCrossRefGoogle Scholar
  51. 51.
    Fujinami RS, von Herrath MG, Christen U, Whitton JL (2006) Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 19:80–94PubMedCrossRefGoogle Scholar
  52. 52.
    Guidotti LG, Chisari FV (2001) Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19:65–91PubMedCrossRefGoogle Scholar
  53. 53.
    Gullestad L, Aass H, Fjeld JG, Wikeby L, Andreassen AK, Ihlen H, Simonsen S, Kjekshus J, Nitter-Hauge S, Ueland T, Lien E, Froland SS, Aukrust P (2001) Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation 103:220–225PubMedGoogle Scholar
  54. 54.
    Hardin JA (2005) Dendritic cells: potential triggers of autoimmunity and targets for therapy. Annals of the Rheumatic Diseases 64:iv86–iv90PubMedCrossRefGoogle Scholar
  55. 55.
    Horwitz MS, La CA, Fine C, Rodriguez E, Ilic A, Sarvetnick N (2000) Pancreatic expression of interferongamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis. Nat Med 6:693–697PubMedCrossRefGoogle Scholar
  56. 56.
    Jahns R, Boivin V, Hein L, Triebel S, Angermann CE, Ertl G, Lohse MJ (2004) Direct evidence for a beta 1- adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 113:1419–1429PubMedCrossRefGoogle Scholar
  57. 57.
    Jahns R, Boivin V, Krapf T, Wallukat G, Boege F, Lohse MJ (2000) Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failureassociated autoantibodies. J Am Coll Cardiol 36:1280–1287PubMedCrossRefGoogle Scholar
  58. 58.
    Jahns R, Boivin V, Siegmund C, Inselmann G, Lohse MJ, Boege F (1999) Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation 99:649–654PubMedGoogle Scholar
  59. 59.
    Kaisho T, Akira S (2001) Dendriticcell function in Toll-like receptorand MyD88-knockout mice. Trends Immunol 22:78–83PubMedCrossRefGoogle Scholar
  60. 60.
    Kaisho T, Akira S (2001) Toll-like receptors and their signaling mechanism in innate immunity. Acta Odontol Scand 59:124–130PubMedCrossRefGoogle Scholar
  61. 61.
    Katz SD, Rao R, Berman JW, Schwarz M, Demopoulos L, Bijou R, LeJemtel TH (1994) Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive heart failure. Relation to nitric oxidedependent vasodilation in the forearm circulation. Circulation 90:12–16PubMedGoogle Scholar
  62. 62.
    Kishimoto C, Abelmann WH (1990) In vivo significance of T cells in the development of Coxsackievirus B3 myocarditis in mice. Immature but antigenspecific T cells aggravate cardiac injury. Circ Res 67:589–598PubMedGoogle Scholar
  63. 63.
    Klein RM, Breuer R, Mundhenke M, Schwartzkopff B, and Strauer BE (1998) Circulating adhesion molecules (cICAM-1, lcVCAM-1) in patients with suspected inflammatory heart muscle disease. Z Kardiol 87(2):84–93PubMedCrossRefGoogle Scholar
  64. 64.
    Klein RM, Jiang H, Niederacher D, Adams O, Du M, Horlitz M, Schley P, Marx R, Lankisch MR, Brehm MU, Strauer BE, Gabbert HE, Scheffold T, and Gulker H (2004) Frequency and quantity of the parvovirus B19 genome in endomyocardial biopsies from patients with suspected myocarditis or idiopathic left ventricular dysfunction. Z Kardiol 93(4):300–309PubMedCrossRefGoogle Scholar
  65. 65.
    Klingel K, Rieger P, Mall G, Selinka HC, Huber M, Kandolf R (1998) Visualization of enteroviral replication in myocardial tissue by ultrastructural in situ hybridization: identification of target cells and cytopathic effects. Lab Invest 78:1227–1237PubMedGoogle Scholar
  66. 66.
    Konstadoulakis MM, Kroumbouzou H, Tsiamis E, Trikas A, Toutouzas P (1993) Clinical significance of antibodies against tropomyosin, actin and myosin in patients with dilated cardiomyopathy. J Clin Lab Immunol 40:61–67PubMedGoogle Scholar
  67. 67.
    Krause EG (1991) Cellular and molecular mechanisms in heart failure. Z Kardiol 80(Suppl 8):13–18PubMedGoogle Scholar
  68. 68.
    Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM (1997) Cardiacspecific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J Card Fail 3:117–124PubMedCrossRefGoogle Scholar
  69. 69.
    Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM (1997) Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 81:627–635PubMedGoogle Scholar
  70. 70.
    Kuhl U, Melzner B, Schafer B, Schultheiss HP, Strauer BE (1991) The Cachannel as cardiac autoantigen. Eur Heart J 12(Suppl D):99–104PubMedGoogle Scholar
  71. 71.
    Kuhl U, Noutsias M, Seeberg B, Schultheiss HP (1996) Immunohistological evidence for a chronic intramyocardial inflammatory process in dilated cardiomyopathy. Heart 75:295–300PubMedGoogle Scholar
  72. 72.
    Kuhl U, Pauschinger M, Bock T, Klingel K, Schwimmbeck CP, Seeberg B, Krautwurm L, Poller W, Schultheiss HP, Kandolf R (2003) Parvovirus B19 infection mimicking acute myocardial infarction. Circulation 108:945–950PubMedCrossRefGoogle Scholar
  73. 73.
    Kuhl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandolf R, Schultheiss HP (2005) High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 111:887–893PubMedCrossRefGoogle Scholar
  74. 74.
    Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP (2003) Interferon- beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107:2793–2798PubMedCrossRefGoogle Scholar
  75. 75.
    Kuhl U, Pauschinger M, Seeberg B, Lassner D, Noutsias M, Poller W, Schultheiss HP (2005) Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 112:1965–1970PubMedCrossRefGoogle Scholar
  76. 76.
    Kurki P, Karjalainen J, Hautanen A, Virtanen I (1989) Desmin antibodies in acute infectious myopericarditis. APMIS 97:527–532PubMedCrossRefGoogle Scholar
  77. 77.
    Kurrer MO, Kopf M, Penninger JM, Eriksson U (2002) Cytokines that regulate autoimmune myocarditis. Swiss Med Wkly 132:408–413PubMedGoogle Scholar
  78. 78.
    Latif N, Baker CS, Dunn MJ, Rose ML, Brady P, Yacoub MH (1993) Frequency and specificity of antiheart antibodies in patients with dilated cardiomyopathy detected using SDSPAGE and western blotting. J Am Coll Cardiol 22:1378–1384PubMedCrossRefGoogle Scholar
  79. 79.
    Latif N, Zhang H, Archard LC, Yacoub MH, Dunn MJ (1999) Characterization of anti-heart antibodies in mice after infection with coxsackie B3 virus. Clin Immunol 91:90–98PubMedCrossRefGoogle Scholar
  80. 80.
    Lauer B, Padberg K, Schultheiss HP, and Strauer BE (1995) [Autoantibodies against cardiac myosin in patients with myocarditis and dilated cardiomyopathy]. Z Kardiol 84(4):301–310PubMedGoogle Scholar
  81. 81.
    Lauer B, Schannwell M, Kuhl U, Strauer BE, Schultheiss HP (2000) Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis. J Am Coll Cardiol 35:11–18PubMedCrossRefGoogle Scholar
  82. 82.
    Lawson CM (2000) Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis. Cell Mol Life Sci 57:552–560PubMedCrossRefGoogle Scholar
  83. 83.
    Lawson CM, O’Donoghue HL, Reed WD (1992) Mouse cytomegalovirus infection induces antibodies which cross-react with virus and cardiac myosin: a model for the study of molecular mimicry in the pathogenesis of viral myocarditis. Immunology 75:513–519PubMedGoogle Scholar
  84. 84.
    Levine B, Kalman J, Mayer L, Fillit HM, Packer M (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236–241PubMedCrossRefGoogle Scholar
  85. 85.
    Liao L, Sindhwani R, Rojkind M, Factor S, Leinwand L, Diamond B (1995) Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity. J Exp Med 181:1123–1131PubMedCrossRefGoogle Scholar
  86. 86.
    Limas CJ, Goldenberg IF, Limas C (1992) Assessment of immune modulation of beta-adrenergic pathways in human dilated cardiomyopathy: influence of methodologic factors. Am Heart J 123:967–970PubMedCrossRefGoogle Scholar
  87. 87.
    Limas CJ, Limas C, Kubo SH, Olivari MT (1990) Anti-beta-receptor antibodies in human dilated cardiomyopathy and correlation with HLA-DR antigens. Am J Cardiol 65:483–487PubMedCrossRefGoogle Scholar
  88. 88.
    Liu HR, Zhao RR, Jiao XY, Wang YY, Fu M (2002) Relationship of myocardial remodeling to the genesis of serum autoantibodies to cardiac β 1- adrenoceptors and muscarinic type 2 acetylcholine receptors in rats. Journal of the American College of Cardiology 39:1866–1873PubMedCrossRefGoogle Scholar
  89. 89.
    Louis A, Cleland JG, Crabbe S, Ford S, Thackray S, Houghton T, Clark A (2001) Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail 3:381–387PubMedCrossRefGoogle Scholar
  90. 90.
    Magnusson Y, Marullo S, Hoyer S, Waagstein F, Andersson B, Vahlne A, Guillet JG, Strosberg AD, Hjalmarson A, Hoebeke J (1990) Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J Clin Invest 86:1658–1663PubMedCrossRefGoogle Scholar
  91. 91.
    Mandi Y, Hogye M, Talha EM, Skolak E, Csanady M (2000) Cytokine production and antibodies against heat shock protein 60 in cardiomyopathies of different origins. Pathobiology 68:150–158PubMedCrossRefGoogle Scholar
  92. 92.
    Manjula BN, Trus BL, Fischetti VA (1985) Presence of two distinct regions in the coiled-coil structure of the streptococcal Pep M5 protein: relationship to mammalian coiled-coil proteins and implications to its biological properties. Proc Natl Acad Sci USA 82:1064–1068PubMedCrossRefGoogle Scholar
  93. 93.
    Marrack P, Kappler J, Mitchell T (1999) Type I interferons keep activated T cells alive. J Exp Med 189:521–530PubMedCrossRefGoogle Scholar
  94. 94.
    Matsui S, Fu ML, Katsuda S, Hayase M, Yamaguchi N, Teraoka K, Kurihara T, Takekoshi N, Murakami E, Hoebeke J, Hjalmarson A (1997) Peptides derived from cardiovascular G-proteincoupled receptors induce morphological cardiomyopathic changes in immunized rabbits. J Mol Cell Cardiol 29:641–655PubMedCrossRefGoogle Scholar
  95. 95.
    Matsui S, Fu ML, Shimizu M, Fukuoka T, Teraoka K, Takekoshi N, Murakami E, Hjalmarson A (1995) Dilated cardiomyopathy defines serum autoantibodies against G-protein-coupled cardiovascular receptors. Autoimmunity 21:85–88PubMedGoogle Scholar
  96. 96.
    McMurray J, Pfeffer MA (2002) New therapeutic options in congestive heart failure: Part II. Circulation 105:2223–2228PubMedCrossRefGoogle Scholar
  97. 97.
    Meldrum DR (1998) Tumor necrosis factor in the heart. Am J Physiol 274:R577–R595PubMedGoogle Scholar
  98. 98.
    Michels VV, Moll PP, Rodeheffer RJ, Miller FA, Jr., Tajik AJ, Burnett JC, Jr., Driscoll DJ, Thibodeau SN, Ansari AA, Herskowitz A (1994) Circulating heart autoantibodies in familial as compared with nonfamilial idiopathic dilated cardiomyopathy. Mayo Clin Proc 69:24–27PubMedGoogle Scholar
  99. 99.
    Mitchell T, Kappler J, Marrack P (1999) Bystander virus infection prolongs activated T cell survival. The Journal of Immunology 162:4527–4535PubMedGoogle Scholar
  100. 100.
    Mobini R, Maschke H, Waagstein F (2004) New insights into the pathogenesis of dilated cardiomyopathy: possible underlying autoimmune mechanisms and therapy. Autoimmun Rev 3:277–284PubMedCrossRefGoogle Scholar
  101. 101.
    Mobini R, Staudt A, Felix SB, Baumann G, Wallukat G, Deinum J, Svensson H, Hjalmarson A, Fu M (2003) Hemodynamic improvement and removal of autoantibodies against beta1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy. J Autoimmun 20:345–350PubMedCrossRefGoogle Scholar
  102. 102.
    Moore KW, de Waal MR, Coffman RL, O'Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765PubMedCrossRefGoogle Scholar
  103. 103.
    Morad M, Davies NW, Ulrich G, Schultheiss HP (1988) Antibodies against ADP-ATP carrier enhance Ca2+ current in isolated cardiac myocytes. Am J Physiol 255:H960–H964PubMedGoogle Scholar
  104. 104.
    Munn DH, Mellor AL (2003) Macrophages and the regulation of self-reactive T cells. Curr Pharm Des 9:257–264PubMedCrossRefGoogle Scholar
  105. 105.
    Neu N, Craig SW, Rose NR, Alvarez F, Beisel KW (1987) Coxsackievirus induced myocarditis in mice: cardiac myosin autoantibodies do not crossreact with the virus. Clin Exp Immunol 69:566–574PubMedGoogle Scholar
  106. 106.
    Neumann DA, Burek CL, Baughman KL, Rose NR, Herskowitz A (1990) Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy. J Am Coll Cardiol 16:839–846PubMedCrossRefGoogle Scholar
  107. 107.
    Neumann DA, Rose NR, Ansari AA, Herskowitz A (1994) Induction of multiple heart autoantibodies in mice with coxsackievirus B3- and cardiac myosininduced autoimmune myocarditis. J Immunol 152:343–350PubMedGoogle Scholar
  108. 108.
    Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322PubMedCrossRefGoogle Scholar
  109. 109.
    Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, Honjo T (2003) Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9:1477–1483PubMedCrossRefGoogle Scholar
  110. 110.
    Okura Y, Takeda K, Honda S, Hanawa H, Watanabe H, Kodama M, Izumi T, Aizawa Y, Seki S, Abo T (1998) Recombinant murine interleukin-12 facilitates induction of cardiac myosin-specific type 1 helper T cells in rats. Circ Res 82:1035–1042PubMedGoogle Scholar
  111. 111.
    Opavsky MA, Penninger J, Aitken K, Wen WH, Dawood F, Mak T, Liu P (1999) Susceptibility to myocarditis is dependent on the response of alphabeta T lymphocytes to coxsackieviral infection. Circ Res 85:551–558PubMedGoogle Scholar
  112. 112.
    Pankuweit S, Portig I, Lottspeich F, Maisch B (1997) Autoantibodies in sera of patients with myocarditis: characterization of the corresponding proteins by isoelectric focusing and N-terminal sequence analysis. J Mol Cell Cardiol 29:77–84PubMedCrossRefGoogle Scholar
  113. 113.
    Pankuweit S, Portig I, Maisch B (2002) Pathophysiology of cardiac inflammation: molecular mechanisms. Herz 27:669–676PubMedCrossRefGoogle Scholar
  114. 114.
    Pauschinger M, Bowles NE, Fuentes- Garcia FJ, Pham V, Kuhl U, Schwimmbeck PL, Schultheiss HP, Towbin JA (1999) Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. Circulation 99:1348–1354PubMedGoogle Scholar
  115. 115.
    Pauschinger M, Doerner A, Kuehl U, Schwimmbeck PL, Poller W, Kandolf R, Schultheiss HP (1999) Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis. Circulation 99:889–895PubMedGoogle Scholar
  116. 116.
    Pauschinger M, Kuhl U, Dorner A, Schieferecke K, Petschauer S, Rauch U, Schwimmbeck PL, Kandolf R, Schultheiss HP (1998) [Detection of enteroviral RNA in endomyocardial biopsies in inflammatory cardiomyopathy and idiopathic dilated cardiomyopathy]. Z Kardiol 87:443–452PubMedCrossRefGoogle Scholar
  117. 117.
    Pauschinger M, Noutsias M, Schultheiss HP, Kuehl U (2006) Inflammation, ECG changes and pericardial effusion: Whom to biopsy in suspected myocarditis? Clin Res Cardiol (in press)Google Scholar
  118. 118.
    Pohlner K, Portig I, Pankuweit S, Lottspeich F, Maisch B (1997) Identification of mitochondrial antigens recognized by antibodies in sera of patients with idiopathic dilated cardiomyopathy by two-dimensional gel electrophoresis and protein sequencing. Am J Cardiol 80:1040–1045PubMedCrossRefGoogle Scholar
  119. 119.
    Pulkki KJ (1997) Cytokines and cardiomyocyte death. Ann Med 29:339–343PubMedGoogle Scholar
  120. 120.
    Qing-Qing W, Yu-Lin W, Hai-Tao Y, Feng-Qin L, You-Peng J, Bo H (2006) Immune Tolerance to Cardiac Myosin Induced by Anti-CD4 Monoclonal Antibody in Autoimmune Myocarditis Rats. J Clin Immunol 26:213–221CrossRefGoogle Scholar
  121. 121.
    Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD (2000) Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102:3060–3067PubMedGoogle Scholar
  122. 122.
    Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P (1996) Report of the 1995 World Health Organization/ International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 93:841–842PubMedGoogle Scholar
  123. 123.
    Rose NR (2002) Mechanisms of autoimmunity. Semin Liver Dis 22:387–394PubMedCrossRefGoogle Scholar
  124. 124.
    Rose NR, Mackay IR (2000) Molecular mimicry: a critical look at exemplary instances in human diseases. Cell Mol Life Sci 57:542–551PubMedCrossRefGoogle Scholar
  125. 125.
    Sakaguchi S, Toda M, Asano M, Itoh M, Morse SS, Sakaguchi N (1996) T cellmediated maintenance of natural self-tolerance: its breakdown as a possible cause of various autoimmune diseases. J Autoimmun 9:211–220PubMedCrossRefGoogle Scholar
  126. 126.
    Sato Y, Matsumori A, Sasayama S (1994) Autoantibodies against vimentin in a murine model of myocarditis. Autoimmunity 18:145–148PubMedCrossRefGoogle Scholar
  127. 127.
    Savelkoul HF, van Ommen R. (1996) Role of IL-4 in persistent IgE formation. Eur Respir J 22(Suppl):67s–71sGoogle Scholar
  128. 128.
    Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J (1995) Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNFalpha and activates immune effector functions. Cytokine 7:251–259PubMedCrossRefGoogle Scholar
  129. 129.
    Schimke I, Muller J, Dandel M, Gremmels HD, Bayer W, Wallukat B, Wallukat G, Hetzer R (2005) Reduced oxidative stress in parallel to improved cardiac performance one year after selective removal of anti-beta 1- adrenoreceptor autoantibodies in patients with idiopathic dilated cardiomyopathy: data of a preliminary study. J Clin Apher 20:137–142PubMedCrossRefGoogle Scholar
  130. 130.
    Schultheiss HP (1993) [Dilated cardiomyopathy- a chronic myocarditis? New aspects on diagnosis and therapy]. Z Kardiol 82(Suppl 4):25–32PubMedGoogle Scholar
  131. 131.
    Schultheiss HP, Kuhl U, Janda I, Melzner B, Ulrich G, Morad M (1988) Antibody-mediated enhancement of calcium permeability in cardiac myocytes. J Exp Med 168:2105–2119PubMedCrossRefGoogle Scholar
  132. 132.
    Schultheiss HP, Schulze K, Schauer R, Witzenbichler B, Strauer BE (1995) Antibody-mediated imbalance of myocardial energy metabolism. A causal factor of cardiac failure? Circ Res 76:64–72PubMedGoogle Scholar
  133. 133.
    Schultheiss HP, Schwimmbeck P, Bolte HD, Klingenberg M (1985) The antigenic characteristics and the significance of the adenine nucleotide translocator as a major autoantigen to antimitochondrial antibodies in dilated cardiomyopathy. Adv Myocardiol 6:311–327PubMedGoogle Scholar
  134. 134.
    Schulze K, Becker BF, Schultheiss HP (1989) Antibodies to the ADP/ATP carrier, an autoantigen in myocarditis and dilated cardiomyopathy, penetrate into myocardial cells and disturb energy metabolism in vivo. Circ Res 64:179–192PubMedGoogle Scholar
  135. 135.
    Schulze K, Witzenbichler B, Christmann C, Schultheiss HP (1999) Disturbance of myocardial energy metabolism in experimental virus myocarditis by antibodies against the adenine nucleotide translocator. Cardiovasc Res 44:91–100PubMedCrossRefGoogle Scholar
  136. 136.
    Schwimmbeck PL, Badorff C, Schultheiss HP, Strauer BE (1994) Transfer of human myocarditis into severe combined immunodeficiency mice. Circ Res 75:156–164PubMedGoogle Scholar
  137. 137.
    Segal BM, Klinman DM, Shevach EM (1997) Microbial products induce autoimmune disease by an IL-12-dependent pathway. J Immunol 158:5087–5090PubMedGoogle Scholar
  138. 138.
    Sliwa K, Skudicky D, Candy G, Wisenbaugh T, Sareli P (1998) Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet 351:1091–1093PubMedCrossRefGoogle Scholar
  139. 139.
    Smith SC, Allen PM (1991) Myosininduced acute myocarditis is a T cellmediated disease. J Immunol 147:2141–2147PubMedGoogle Scholar
  140. 140.
    Staudt A, Bohm M, Knebel F, Grosse Y, Bischoff C, Hummel A, Dahm JB, Borges A, Jochmann N, Wernecke KD, Wallukat G, Baumann G, Felix SB (2002) Potential role of autoantibodies belonging to the immunoglobulin G-3 subclass in cardiac dysfunction among patients with dilated cardiomyopathy. Circulation 106:2448–2453PubMedCrossRefGoogle Scholar
  141. 141.
    Staudt A, Mobini R, Fu M, Grosse Y, Stangl V, Stangl K, Thiele A, Baumann G, Felix SB (2001) beta(1)-Adrenoceptor antibodies induce positive inotropic response in isolated cardiomyocytes. Eur J Pharmacol 423:115–119PubMedCrossRefGoogle Scholar
  142. 142.
    Staudt A, Staudt Y, Dorr M, Bohm M, Knebel F, Hummel A, Wunderle L, Tiburcy M, Wernecke KD, Baumann G, Felix SB (2004) Potential role of humoral immunity in cardiac dysfunction of patients suffering from dilated cardiomyopathy. J Am Coll Cardiol 44:829–836PubMedCrossRefGoogle Scholar
  143. 143.
    Staudt A, Schaper F, Stangl V, Plagemann A, Bohm M, Merkel K, Wallukat G, Wernecke KD, Stangl K, Baumann G, Felix SB (2001) Immunohistological Changes in Dilated Cardiomyopathy Induced by Immunoadsorption Therapy and Subsequent Immunoglobulin Substitution. Circulation 103:2681–2686PubMedGoogle Scholar
  144. 144.
    Staudt Y, Mobini R, Fu M, Felix SB, Kuhn JP, Staudt A (2003) Beta 1-adrenoceptor antibodies induce apoptosis in adult isolated cardiomyocytes. Eur J Pharmacol 466:1–6PubMedCrossRefGoogle Scholar
  145. 145.
    Sterin-Borda L, Cremaschi G, Pascual J, Genaro A, Borda E (1984) Alloimmune IgG binds and modulates cardiac beta-adrenoceptor activity. Clin Exp Immunol 58:223–228PubMedGoogle Scholar
  146. 146.
    Stille-Siegener M, Heim A, Figulla HR (1995) Subclassification of dilated cardiomyopathy and interferon treatment. Eur Heart J 16 Suppl O:147– 149PubMedGoogle Scholar
  147. 147.
    Tang Z, McGowan BS, Huber SA, McTiernan CF, Addya S, Surrey S, Kubota T, Fortina P, Higuchi Y, Diamond MA, Wyre DS, Feldman AM (2004) Gene expression profiling during the transition to failure in TNFalpha overexpressing mice demonstrates the development of autoimmune myocarditis. J Mol Cell Cardiol 36:515–530PubMedCrossRefGoogle Scholar
  148. 148.
    Torre-Amione G, Bozkurt B, Deswal A, Mann DL (1999) An overview of tumor necrosis factor alpha and the failing human heart. Curr Opin Cardiol 14:206–210PubMedCrossRefGoogle Scholar
  149. 149.
    Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL (1996) Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 27:1201–1206PubMedCrossRefGoogle Scholar
  150. 150.
    Tough DF (2004) Type I interferon as a link between innate and adaptive immunity through dendritic cell stimulation. Leuk Lymphoma 45:257–264PubMedCrossRefGoogle Scholar
  151. 151.
    Tough DF, Borrow P, Sprent J (1996) Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272:1947–1950PubMedCrossRefGoogle Scholar
  152. 152.
    Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13:251–276PubMedCrossRefGoogle Scholar
  153. 153.
    Trinchieri G, Pflanz S, Kastelein RA (2003) The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19:641–644PubMedCrossRefGoogle Scholar
  154. 154.
    Wada H, Saito K, Kanda T, Kobayashi I, Fujii H, Fujigaki S, Maekawa N, Takatsu H, Fujiwara H, Sekikawa K, Seishima M (2001) Tumor necrosis factor-alpha (TNF-alpha) plays a protective role in acute viralmyocarditis in mice: A study using mice lacking TNF-alpha. Circulation 103:743–749PubMedGoogle Scholar
  155. 155.
    Wallukat G, Morwinski R, Magnusson Y, Hoebeke J, and Wollenberger A (1992) Autoantibodies against the beta 1-adrenergic receptor in myocarditis and dilated cardiomyopathy: localization of two epitopes. Z Kardiol 81(Suppl 4):79–83PubMedGoogle Scholar
  156. 156.
    Wallukat G, Fu ML, Magnusson Y, Hjalmarson A, Hoebeke J, Wollenberger A (1996) Agonistic effects of antipeptide antibodies and autoantibodies directed against adrenergic and cholinergic receptors: absence of desensitization. Blood Press Suppl 3:31–36CrossRefGoogle Scholar
  157. 157.
    Wallukat G, Wollenberger A (1987) Effects of the serum gamma globulin fraction of patients with allergic asthma and dilated cardiomyopathy on chronotropic beta adrenoceptor function in cultured neonatal rat heart myocytes. Biomed Biochim Acta 46:S634–S639PubMedGoogle Scholar
  158. 158.
    Wang Z, Liao Y, Dong J, Li S, Wang J, Fu ML (2003) Clinical significance and pathogenic role of anti-cardiac myosin autoantibody in dilated cardiomyopathy. Chin Med J (Engl ) 116:499–502PubMedGoogle Scholar
  159. 159.
    Warraich RS, Noutsias M, Kazak I, Seeberg B, Dunn MJ, Schultheiss HP, Yacoub MH, Kuhl U, Kasac I (2002) Immunoglobulin G3 cardiac myosin autoantibodies correlate with left ventricular dysfunction in patients with dilated cardiomyopathy: immunoglobulin G3 and clinical correlates. Am Heart J 143:1076–1084PubMedCrossRefGoogle Scholar
  160. 160.
    Watanabe K, Nakazawa M, Fuse K, Hanawa H, Kodama M, Aizawa Y, Ohnuki T, Gejyo F, Maruyama H, Miyazaki J (2001) Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation. Circulation 104:1098–1100PubMedGoogle Scholar
  161. 161.
    Wolff PG, Kuhl U, Schultheiss HP (1989) Laminin distribution and autoantibodies to laminin in dilated cardiomyopathy and myocarditis. Am Heart J 117:1303–1309PubMedCrossRefGoogle Scholar
  162. 162.
    Zwaka TP, Manolov D, Ozdemir C, Marx N, Kaya Z, Kochs M, Hoher M, Hombach V, Torzewski J (2002) Complement and dilated cardiomyopathy: a role of sublytic terminal complement complex-induced tumor necrosis factoralpha synthesis in cardiac myocytes. Am J Pathol 161:449–457PubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2007

Authors and Affiliations

  • Angela Kallwellis-Opara
    • 1
  • Andrea Dörner
    • 1
  • Wolfgang-Christian Poller
    • 1
  • Michel Noutsias
    • 1
  • Uwe Kühl
    • 1
  • Heinz-Peter Schultheiss
    • 1
  • Mathias Pauschinger
    • 1
    Email author
  1. 1.Charité – Universitätsmedizin Berlin, Campus Benjamin-FranklinMedizinische Klinik II, Abteilung für Kardiologie und PneumologieBerlinGermany

Personalised recommendations