Autoantibodies Against Cardiac Troponin I Are Responsible for Dilated Cardiomyopathy in PD-1-deficient Mice

Nat Med. 2003 Dec;9(12):1477-83. doi: 10.1038/nm955. Epub 2003 Nov 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antigens, CD
  • Antigens, Surface / genetics
  • Antigens, Surface / immunology*
  • Apoptosis Regulatory Proteins
  • Autoantibodies / metabolism*
  • Base Sequence
  • Calcium Signaling
  • Cardiomyopathy, Dilated / etiology*
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / immunology*
  • Cardiomyopathy, Dilated / metabolism
  • DNA, Complementary / genetics
  • Humans
  • Mice
  • Mice, Inbred A
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • Myocytes, Cardiac / immunology
  • Myocytes, Cardiac / metabolism
  • Programmed Cell Death 1 Receptor
  • Rats
  • Rats, Wistar
  • Troponin I / immunology*

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • Autoantibodies
  • DNA, Complementary
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Troponin I