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

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

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Abstract

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.

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Acknowledgements

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

Affiliations

  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

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The authors declare no competing financial interests.

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Correspondence to Tasuku Honjo.

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DOI

https://doi.org/10.1038/nm955

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