Article | Published:

Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice

Nature Medicine volume 9, pages 14771483 (2003) | Download Citation



We recently reported that mice deficient in the programmed cell death-1 (PD-1) immunoinhibitory coreceptor develop autoimmune dilated cardiomyopathy (DCM), with production of high-titer autoantibodies against a heart-specific, 30-kDa protein. In this study, we purified the 30-kDa protein from heart extract and identified it as cardiac troponin I (cTnI), encoded by a gene in which mutations can cause familial hypertrophic cardiomyopathy (HCM). Administration of monoclonal antibodies to cTnI induced dilatation and dysfunction of hearts in wild-type mice. Monoclonal antibodies to cTnI stained the surface of cardiomyocytes and augmented the voltage-dependent L-type Ca2+ current of normal cardiomyocytes. These findings suggest that antibodies to cTnI induce heart dysfunction and dilatation by chronic stimulation of Ca2+ influx in cardiomyocytes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 93, 841–842 (1996).

  2. 2.

    et al. Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on heart failure research. Circulation 95, 766–770 (1997).

  3. 3.

    et al. Epidemiologic and clinical characteristics of cardiomyopathies in Japan. Circ. J. 66, 323–236 (2002).

  4. 4.

    , & Concepts of autoimmunity applied to idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 22, 1385–1388 (1993).

  5. 5.

    et al. 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, 77–84 (1997).

  6. 6.

    et al. The ADP/ATP carrier as a mitochondrial auto-antigen—facts and perspectives. Ann. NY Acad. Sci. 488, 44–64 (1986).

  7. 7.

    et al. Diagnostic relevance of humoral and cytotoxic immune reactions in primary and secondary dilated cardiomyopathy. Am. J. Cardiol. 52, 1072–1078 (1983).

  8. 8.

    et al. Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy. J. Am. Coll. Cardiol. 16, 839–846 (1990).

  9. 9.

    et al. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 103, 2681–2686 (2001).

  10. 10.

    & An experimental model for congestive heart failure after encephalomyocarditis virus myocarditis in mice. Circulation 65, 1230–1235 (1982).

  11. 11.

    et al. Heart-specific autoantibodies induced by coxsackievirus B3: identification of heart autoantigens. Clin. Immunol. Immunopathol. 43, 129–139 (1987).

  12. 12.

    et al. Peptides derived from cardiovascular G-protein-coupled receptors induce morphological cardiomyopathic changes in immunized rabbits. J. Mol. Cell. Cardiol. 29, 641–655 (1997).

  13. 13.

    et al. Cardiac myosin induces myocarditis in genetically predisposed mice. J. Immunol. 139, 3630–3636 (1987).

  14. 14.

    , & Cardiac myosin-induced myocarditis. Heart autoantibodies are not involved in the induction of the disease. J. Immunol. 145, 4094–4100 (1990).

  15. 15.

    , & New regulatory co-receptors: inducible co-stimulator and PD-1. Curr. Opin. Immunol. 14, 779–782 (2002).

  16. 16.

    et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001).

  17. 17.

    & Cell 104, 557–567 (2001).

  18. 18.

    et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat. Genet. 16, 379–382 (1997).

  19. 19.

    Troponin I, stunning, hypertrophy, and failure of the heart. Circ. Res. 84, 122–124 (1999).

  20. 20.

    The role of cytoskeletal proteins in cardiomyopathies. Curr. Opin. Cell. Biol. 10, 131–139 (1998).

  21. 21.

    et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N. Engl. J. Med. 343, 1688–1696 (2000).

  22. 22.

    & Troponin and tropomyosin: proteins that switch on and tune in the activity of cardiac myofilaments. Circ. Res. 83, 471–480 (1998).

  23. 23.

    et al. Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12. Nature 391, 489–492 (1998).

  24. 24.

    et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

  25. 25.

    et al. Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. J. Physiol. 525, 483–498 (2000).

  26. 26.

    et al. Antibody-mediated enhancement of calcium permeability in cardiac myocytes. J. Exp. Med. 168, 2105–2119 (1988).

  27. 27.

    et al. β1-adrenoceptor antibodies induce positive inotropic response in isolated cardiomyocytes. Eur. J. Pharmacol. 423, 115–119 (2001).

  28. 28.

    et al. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. J. Am. Coll. Cardiol. 39, 646–652 (2002).

  29. 29.

    et al. Transgenic mouse model of stunned myocardium. Science 287, 488–491 (2000).

  30. 30.

    Myocardial markers of injury. Evolution and insights. Am. J. Clin. Pathol. 105, 305–320 (1996).

  31. 31.

    et al. Disturbance of myocardial energy metabolism in experimental virus myocarditis by antibodies against the adenine nucleotide translocator. Cardiovasc. Res. 44, 91–100 (1999).

  32. 32.

    et al. ESDN, a novel neuropilin-like membrane protein cloned from vascular cells with the longest secretory signal sequence among eukaryotes, is up-regulated after vascular injury. J. Biol. Chem. 276, 34105–34114 (2001).

  33. 33.

    et al. Localization of rabphilin-3A on the synaptic vesicle. Biochem. Biophys. Res. Commun. 202, 1235–1243 (1994).

  34. 34.

    et al. Left ventricular pressure-volume relationship in a murine model of congestive heart failure due to acute viral myocarditis. J. Am. Coll. Cardiol. 40, 1506–1514 (2002).

  35. 35.

    , , & Slow inactivation of cardiac L-type Ca2+ channel induced by cold acclimation of guinea pig. Am. J. Physiol. 274, R348–R356 (1998).

  36. 36.

    & Calcium tolerant ventricular myocytes prepared by preincubation in a “KB medium”. Pflugers. Arch. 395, 6–18 (1982).

  37. 37.

    et al. Electrical properties of individual cells isolated from adult rat ventricular myocardium. J. Physiol. 302, 131–153 (1980).

  38. 38.

    et al. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers. Arch. 391, 85–100 (1981).

Download references


We thank A. Noma, K. Yamauchi-Takihara, K. Kobuke, T. Nakamura, I. Okazaki and members of the Honjo laboratory for helpful discussions; S. Shibayama, Y. Odagaki and M. Matsuo (Ono Pharmaceutical) and APRO Life Science Institute for assistance with antigen determination; and E. Inoue for technical assistance. This work was supported by a Center of Excellence Grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan. J.W. is a research fellow of the Japan Society for the Promotion of Science.

Author information


  1. Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.

    • Taku Okazaki
    • , Jian Wang
    •  & Tasuku Honjo
  2. Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.

    • Yoshimasa Tanaka
    • , Masayoshi Ishida
    •  & Nagahiro Minato
  3. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan.

    • Yoshimasa Tanaka
  4. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.

    • Ryosuke Nishio
    •  & Akira Matsumori
  5. Division of Emergency Medicine, Kyoto University Hospital, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

    • Ryosuke Nishio
  6. Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.

    • Tamotsu Mitsuiye
  7. Department of Anatomy, Graduate School of Medicine, Mie University, Edobashi, Tsu, Mie, 514-8507, Japan.

    • Akira Mizoguchi
  8. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.

    • Hiroshi Hiai


  1. Search for Taku Okazaki in:

  2. Search for Yoshimasa Tanaka in:

  3. Search for Ryosuke Nishio in:

  4. Search for Tamotsu Mitsuiye in:

  5. Search for Akira Mizoguchi in:

  6. Search for Jian Wang in:

  7. Search for Masayoshi Ishida in:

  8. Search for Hiroshi Hiai in:

  9. Search for Akira Matsumori in:

  10. Search for Nagahiro Minato in:

  11. Search for Tasuku Honjo in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tasuku Honjo.

Supplementary information

About this article

Publication history





Further reading