Antibodies to the ADP/ATP carrier, an autoantigen in myocarditis and dilated cardiomyopathy, penetrate into myocardial cells and disturb energy metabolism in vivo.
We identified the ADP/ATP carrier, located within the inner mitochondrial membrane, to be an organ- and conformation-specific autoantigen in myocarditis and dilated cardiomyopathy. We also showed that autoantibodies to the ADP/ATP carrier inhibit the nucleotide transport in vitro. Specific binding of the autoantibodies to the carrier was demonstrated by radioimmunoassay and the immunoblot technique; the inhibition of the nucleotide transport was determined by the inhibitor stop method. To establish if these autoantibodies might also affect cardiac energy metabolism in vivo, we measured whether they are capable of penetrating into myocytes and whether subcellular ATP/ADP ratios and phosphorylation potentials of ATP change in hearts of guinea pigs that have been immunized with the isolated ADP/ATP carrier. An intracellular deposition of autoantibodies was observed by direct immunofluorescence and by immunoperoxidase staining on cryosections of the myocardial tissue of animals immunized with the ADP/ATP carrier. Furthermore, binding of autoantibodies to mitochondrial membrane structures was shown by immunoelectron-microscopic methods. The cytosolic and intramitochondrial distribution of adenine nucleotides in stimulated, isolated perfused hearts of guinea pigs immunized with the ADP/ATP carrier was measured by nonaqueous fractionation. Compared with controls performing equal external heart work, the cytosolic ATP decreased in the immunized animals, whereas the mitochondrial ATP increased strongly; ADP concentrations showed an opposite change. Thus, a resultant cytosolic decrease and a marked mitochondrial increase of the ATP/ADP ratio was established. As a consequence, the cytosolic-mitochondrial phosphorylation potential of ATP was diminished. These findings demonstrate that antibodies against intracellular antigens are able to penetrate into living cells, and that autoimmunity to the ADP/ATP carrier may contribute to the pathophysiology of myocarditis and dilated cardiomyopathy by causing an autoantibody-mediated imbalance between intracellular energy delivery and demand.
Schulze
K
K
Department of Internal Medicine, Klinikum Grosshadern, Munich, Federal Republic of Germany.
Becker
B F
BF
Schultheiss
H P
HP
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology*; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D004734:Energy Metabolism; D006168:Guinea Pigs; D008929:Mitochondria, Heart / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000276:immunology*; D009205:Myocarditis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009713:Nucleotidyltransferases / Q000276:immunology*
D000906:Antibodies; D001324:Autoantigens; D000244:Adenosine Diphosphate; D000226:Mitochondrial ADP, ATP Translocases; D009713:Nucleotidyltransferases