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.
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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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DOI: https://doi.org/10.1038/nm955
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