Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 May 1;97(9):2057–2062. doi: 10.1172/JCI118642

Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice.

C L Pummerer 1, K Luze 1, G Grässl 1, K Bachmaier 1, F Offner 1, S K Burrell 1, D M Lenz 1, T J Zamborelli 1, J M Penninger 1, N Neu 1
PMCID: PMC507280  PMID: 8621795

Abstract

Immunization with cardiac myosin induces T cell-mediated myocarditis in genetically predisposed mice and serves as a model for autoimmune heart disease. This study was undertaken to identify pathogenic epitopes on the myosin molecule. Our approach was based on the comparison of the pathogenicity between cardiac (alpha-)myosin and soleus muscle (beta-)myosin. We show that alpha-myosin is the immunodominant isoform and induces myocarditis at high severity and prevalence whereas beta-myosin induces little disease. Therefore the immunodominant epitopes of alpha-myosin must reside in regions of different amino acid sequence between alpha- and beta-myosin isoforms. Cardiac myosin peptides corresponding to these regions of difference were synthesized and tested for their ability to induce inflammatory heart disease. Three pathogenic peptides were identified. One peptide that is located in the head portion of the molecule induced severe myocarditis, whereas two others that reside in the rod portion possessed only minor pathogenicity. The identification of pathogenic epitopes on the cardiac myosin molecule will allow detailed studies on the recognition of this antigen by the immune system and might be used to downmodulate ongoing heart disease.

Full Text

The Full Text of this article is available as a PDF (378.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Caforio A. L., Grazzini M., Mann J. M., Keeling P. J., Bottazzo G. F., McKenna W. J., Schiaffino S. Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation. 1992 May;85(5):1734–1742. doi: 10.1161/01.cir.85.5.1734. [DOI] [PubMed] [Google Scholar]
  2. Donermeyer D. L., Beisel K. W., Allen P. M., Smith S. C. Myocarditis-inducing epitope of myosin binds constitutively and stably to I-Ak on antigen-presenting cells in the heart. J Exp Med. 1995 Nov 1;182(5):1291–1300. doi: 10.1084/jem.182.5.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Emerson C. P., Jr, Bernstein S. I. Molecular genetics of myosin. Annu Rev Biochem. 1987;56:695–726. doi: 10.1146/annurev.bi.56.070187.003403. [DOI] [PubMed] [Google Scholar]
  4. Franco A., Southwood S., Arrhenius T., Kuchroo V. K., Grey H. M., Sette A., Ishioka G. Y. T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. Eur J Immunol. 1994 Apr;24(4):940–946. doi: 10.1002/eji.1830240424. [DOI] [PubMed] [Google Scholar]
  5. Huber S. A. Viral myocarditis--a tale of two diseases. Lab Invest. 1992 Jan;66(1):1–3. [PubMed] [Google Scholar]
  6. Izumo S., Nadal-Ginard B., Mahdavi V. All members of the MHC multigene family respond to thyroid hormone in a highly tissue-specific manner. Science. 1986 Feb 7;231(4738):597–600. doi: 10.1126/science.3945800. [DOI] [PubMed] [Google Scholar]
  7. Liao L., Sindhwani R., Leinwand L., Diamond B., Factor S. Cardiac alpha-myosin heavy chains differ in their induction of myocarditis. Identification of pathogenic epitopes. J Clin Invest. 1993 Dec;92(6):2877–2882. doi: 10.1172/JCI116909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. McNally E. M., Kraft R., Bravo-Zehnder M., Taylor D. A., Leinwand L. A. Full-length rat alpha and beta cardiac myosin heavy chain sequences. Comparisons suggest a molecular basis for functional differences. J Mol Biol. 1989 Dec 5;210(3):665–671. doi: 10.1016/0022-2836(89)90141-1. [DOI] [PubMed] [Google Scholar]
  9. Morkin E. Regulation of myosin heavy chain genes in the heart. Circulation. 1993 May;87(5):1451–1460. doi: 10.1161/01.cir.87.5.1451. [DOI] [PubMed] [Google Scholar]
  10. Nadal-Ginard B., Mahdavi V. Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J Clin Invest. 1989 Dec;84(6):1693–1700. doi: 10.1172/JCI114351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Neu N., Craig S. W., Rose N. R., Alvarez F., Beisel K. W. Coxsackievirus induced myocarditis in mice: cardiac myosin autoantibodies do not cross-react with the virus. Clin Exp Immunol. 1987 Sep;69(3):566–574. [PMC free article] [PubMed] [Google Scholar]
  12. Neu N., Rose N. R., Beisel K. W., Herskowitz A., Gurri-Glass G., Craig S. W. Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol. 1987 Dec 1;139(11):3630–3636. [PubMed] [Google Scholar]
  13. Olinde K. D., O'Connell J. B. Inflammatory heart disease: pathogenesis, clinical manifestations, and treatment of myocarditis. Annu Rev Med. 1994;45:481–490. doi: 10.1146/annurev.med.45.1.481. [DOI] [PubMed] [Google Scholar]
  14. Pummerer C., Berger P., Frühwirth M., Ofner C., Neu N. Cellular infiltrate, major histocompatibility antigen expression and immunopathogenic mechanisms in cardiac myosin-induced myocarditis. Lab Invest. 1991 Nov;65(5):538–547. [PubMed] [Google Scholar]
  15. Quinn-Laquer B. K., Kennedy J. E., Wei S. J., Beisel K. W. Characterization of the allelic differences in the mouse cardiac alpha-myosin heavy chain coding sequence. Genomics. 1992 May;13(1):176–188. doi: 10.1016/0888-7543(92)90218-h. [DOI] [PubMed] [Google Scholar]
  16. Sartorelli V., Kurabayashi M., Kedes L. Muscle-specific gene expression. A comparison of cardiac and skeletal muscle transcription strategies. Circ Res. 1993 May;72(5):925–931. doi: 10.1161/01.res.72.5.925. [DOI] [PubMed] [Google Scholar]
  17. Schiaffino S., Reggiani C. Myosin isoforms in mammalian skeletal muscle. J Appl Physiol (1985) 1994 Aug;77(2):493–501. doi: 10.1152/jappl.1994.77.2.493. [DOI] [PubMed] [Google Scholar]
  18. Shiverick K. T., Thomas L. L., Alpert N. R. Purification of cardiac myosin. Application to hypertrophied myocardium. Biochim Biophys Acta. 1975 May 30;393(1):124–133. doi: 10.1016/0005-2795(75)90222-6. [DOI] [PubMed] [Google Scholar]
  19. Sloan-Lancaster J., Allen P. M. Significance of T-cell stimulation by altered peptide ligands in T cell biology. Curr Opin Immunol. 1995 Feb;7(1):103–109. doi: 10.1016/0952-7915(95)80035-2. [DOI] [PubMed] [Google Scholar]
  20. Smith S. C., Allen P. M. Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9131–9135. doi: 10.1073/pnas.89.19.9131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Smith S. C., Allen P. M. Myosin-induced acute myocarditis is a T cell-mediated disease. J Immunol. 1991 Oct 1;147(7):2141–2147. [PubMed] [Google Scholar]
  22. Wauben M. H., Boog C. J., van der Zee R., Joosten I., Schlief A., van Eden W. Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone. J Exp Med. 1992 Sep 1;176(3):667–677. doi: 10.1084/jem.176.3.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wegmann K. W., Zhao W., Griffin A. C., Hickey W. F. Identification of myocarditogenic peptides derived from cardiac myosin capable of inducing experimental allergic myocarditis in the Lewis rat. The utility of a class II binding motif in selecting self-reactive peptides. J Immunol. 1994 Jul 15;153(2):892–900. [PubMed] [Google Scholar]
  24. Woodruff J. F. Viral myocarditis. A review. Am J Pathol. 1980 Nov;101(2):425–484. [PMC free article] [PubMed] [Google Scholar]
  25. Zhao W., Wegmann K. W., Trotter J. L., Ueno K., Hickey W. F. Identification of an N-terminally acetylated encephalitogenic epitope in myelin proteolipid apoprotein for the Lewis rat. J Immunol. 1994 Jul 15;153(2):901–909. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES