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

Nature Medicine volume 9, pages 1477–1483 (2003)Cite this article

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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Figure 1: Purification and identification of the 30-kDa autoantigen.
Figure 2: Immunological characterization of cTnI.
Figure 3: Hemodynamics.
Figure 4: Electrophysiological analyses.

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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.

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Authors and 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, 514-8507, Mie, 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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  1. Taku Okazaki
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Correspondence to Tasuku Honjo.

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Okazaki, T., Tanaka, Y., Nishio, R. et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9, 1477–1483 (2003). https://doi.org/10.1038/nm955

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