Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice.
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.
Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.
Taku
T
Okazaki
Yoshimasa
Y
Tanaka
Ryosuke
R
Nishio
Tamotsu
T
Mitsuiye
Akira
A
Mizoguchi
Jian
J
Wang
Masayoshi
M
Ishida
Hiroshi
H
Hiai
Akira
A
Matsumori
Nagahiro
N
Minato
Tasuku
T
Honjo
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies / Q000378:metabolism*; D001483:Base Sequence; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D051381:Rats; D017208:Rats, Wistar; D019210:Troponin I / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D018076:DNA, Complementary; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D019210:Troponin I