Antibodies to the ADP/ATP carrier, an autoantigen in myocarditis and dilated cardiomyopathy, penetrate into myocardial cells and disturb energy metabolism in vivo.

Abstract

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 nudeotide transport in vitro. Specific binding of the autoantibodies to the carrier was demonstrated by radioimmunoassay and the immunoblot technique; the inhibition of the nudeotide 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 inununofluorescence and by immunoperoxldase staining on cryosectlons 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 cytosolicmitochondrial 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. may already be inactivated or continuing as a smoldering process. 6 Indeed, virus persistence has been observed in the hearts of patients with dilated cardiomyopathy who previously suffered from myocarditis.7 Thus, the virus infection may initiate an autoimmune process through antigenic determinants shared by the virus and the host cell or by altering the host's immune system, thereby causing the release or the expression of sequestered antigens.No reports on a possible role of autoantigens in myocarditis and dilated cardiomyopathy exist to date. However, we recently showed that patients with these diseases have autoantibodies against the ADP/ATP carrier, a protein in the inner mitochondria! membrane.8 -10 This transport protein is of great importance for the energy metabolism of the eukaryotic cell.11 It is responsible for both the by guest on May 12, 2018

Myopathy with mitochondrial alterations in patients with primary biliary cirrhosis and antimitochondrial antibodies

“…In certain patients with idiopathic dilated cardiomyopathies, autoantibodies directed against carrier proteins located on the inner mitochondrial membrane can inhibit the transport function of these enzymes and may contribute to the pathogenesis of cardiac dysfunction (29,30). Both patients in the present study had evidence of severe dilated cardiomyopathy .…”

Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac function.

“…First technique in the hearts of previously immunized animals. 7 The fourth possibility of how antibodies can inhibit carrier function is supported by the observation of a cross-reactivity between the ADP-ATP carrier and the calcium channel, shown by immunological, electrophysiological, and functional methods.30,31 It could be demonstrated that carrierspecific antibodies bind specifically on the calcium channel of the cell surface and enhance the calcium influx into the cell.30'31 Thus, in vivo, these antibodies could possibly induce a chronic calcium overload that also could influence indirectly the carrier function because an increased intracellular calcium might decrease the phosphorylation potential difference over the inner mitochondrial membrane.…”

“…As a consequence, the mitochondrial value of the phosphorylation potential of ATP was markedly higher and the cytosolic value was lower than in the hearts of nonimmunized control animals. 7 These data indicate that the autoantibodies found in patients with myocarditis and dilated cardiomyopathy may not be merely an epiphenomenon. Furthermore, our results provide first evidence for a possible novel mechanism of an immunologically mediated dysfunction of the myocardial cell, namely, due to energy deficiency.…”

Mimicry and Antibody-Mediated Cell Signaling in Autoimmune Myocarditis

“…Circulating cardiac autoantibodies to CM and other heart-specific autoantigens are markers of autoimmunity in human myocarditis (11,12,(32)(33)(34)(35)(36). In mice, deposition of CM-reactive Abs in the myocardium was detected after immunization with CM (26).…”