Functional analysis of autoantibodies against ADP/ATP carrier from dilated cardiomyopathy

doi:10.1016/0167-5273(96)02594-6

International Journal of Cardiology

Volume 54, Issue 2, May 1996, Pages 165-169

https://doi.org/10.1016/0167-5273(96)02594-6 Get rights and content

Abstract

The aim of this article is to briefly review the immunological features of the autoantibodies against ADP/ATP carrier from dilated cardiomyopathy and the potential role of the autoantibodies in cardiac tissue injury. The autoantibodies against ADP/ATP carrier were found with very high frequency in patients with dilated cardiomyopathy, and had disease- and organ-specificity. The autoantibodies cross-reacted with subunits of the calcium channel on the cardiac cell membrane. There is a close correlation between the autoantibody-titer and the hemodynamic function in patients with dilated cardiomyopathy. It can be postulated that after an autoimmune response is initiated, the circulating autoantibodies against ADP/ATP carrier disturb myocardial energy metabolism, and enhance calcium influx and calcium overload in cardiac myocytes, resulting in progressive myocyte damage. These findings indicate a new immunopathological mechanism in dilated cardiomyopathy.

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Anti-adenine nucleotide translocator (ANT) autoantibodies are related to the development of Coxsackievirus B3 (CVB3)-triggered acute viral myocarditis (AVMC). Recently, studies suggested that IL-17 especially produced by a novel CD4⁺ Th-cell subset Th17 cells contributed to the production of pathogenic autoantibodies in some autoimmune diseases. However, the pathogenic role of IL-17 in AVMC remains largely unknown. In this study, we investigated whether IL-17 was associated with the disease progression and the production of anti-ANT autoantibodies in AVMC mouse model. The results showed that IL-17 monoclonal antibody (mAb)-treated AVMC mice had decreased HW/BW, reduced serum CK-MB activity and improved pathological score of heart sections along with the reduction of circulating IL-17 level and serum anti-ANT autoantibodies. The correlation index of serum IL-17 concentration and anti-ANT-autoantibody level was 0.874, p < 0.01. In addition, the experimental results in vitro further proved that IL-17mAb could inhibit the proliferation of CD19⁺ B lymphocytes and the secretion of anti-ANT autoantibodies. Our data suggested that IL-17 was related to the disease progression in AVMC mouse model by regulating the production of autoantibodies and blocking IL-17 might represent a promising novel therapeutic approach.
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The pathophysiology of viral myocarditis is still a matter of debate. Humoral autoimmunity in postviral heart disease remains an attractive but complex hypothesis. Antigenic mimicry with or without cytolytic antibody properties has been shown to play a role in the immunopathogenesis of myocarditis with respect to sarcolemmal/myolemmal epitopes (including the beta-receptor), myosin and some mitochondrial proteins including the antinucleotide translocator (ANT)-carrier and dihydrolipoamid dehydrogenase. Today, refined two-dimensional Western blots are able to identify receptors and enzymes that are target of a humoral immune response or the consequence of an “immunization process.” A humoral immune response to an invading agent will most likely lead to immunodestruction first. After conversion to IgG, the continuing antibody response may indicate the healing or healed process and last for many years or life-long. This paper reviews our present knowledge on the humoral immune response in myocarditis and its interplay with the viral agents and the other components of the immune system.
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Citation Excerpt :
In this case, the AMAAB could serve as a marker of an autoimmunologic process in the patients. Another explanation would be that in AMAAB(−) patients, autoantibodies against other cardiac antigens (10–14)may be responsible for the development of chronic myocarditis and that these autoantibodies may have different effects on cardiac function (17,19). However, it cannot be overlooked that the AMAAB themselves may influence cardiac function via a yet unknown mechanism.
OBJECTIVES
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Patients with myocarditis often show autoantibodies against cardiac myosin. The clinical and pathophysiologic significance of these antimyosin autoantibodies (AMAAB) is yet unknown. The results from studies comparing the clinical course and the development of left ventricular function in patients with chronic myocarditis with or without AMAAB are not yet available.
METHODS
Thirty-three patients with biopsy proven chronic myocarditis underwent analysis of AMAAB, right and left heart catheterization and left ventriculography at baseline and after six months. Left ventricular volumes and ejection fraction as well as the time constant of left ventricular relaxation “tau” and the constant of myocardial stiffness “b” were determined at baseline and at follow-up.
RESULTS
In 17 (52%) patients, AMAAB could be detected at baseline. After six months, AMAAB were still found in 13 (76%) initially antibody-positive patients. No initially antibody-negative (n = 16) patient developed AMAAB during follow-up. Clinical symptoms improved slightly in antibody-negative patients and remained stable in antibody-positive patients. Left ventricular ejection fraction developed significantly better in antibody-negative patients (+8.9 ± 10.1%) compared with antibody-positive patients (−0.1 ± 9.4%) (p < 0.012). Stroke volume (SV) and stroke volume index (SVI) also improved in antibody-negative patients (SV: +20 ± 31 ml; SVI: +10 ± 17 ml) compared with antibody-positive patients (SV: −14 ± 43 ml; SVI: −8 ± 22 ml) (SV: p < 0.015; SVI: p < 0.016). Left ventricular end-diastolic and end-systolic volumes and the time constant of left ventricular relaxation “tau” did not change significantly different in antibody-positive and antibody-negative patients. The constant of myocardial stiffness “b” improved significantly in antibody-negative patients (−6.1 ± 10.8) compared with antibody-positive patients (+7.3 ± 22.6) (p < 0.040). Analyzing only the persistently antibody-positive patients yielded essentially the same results.
CONCLUSIONS
Antimyosin autoantibodies are associated with worse development of left ventricular systolic function and diastolic stiffness in patients with chronic myocarditis.
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Functional analysis of autoantibodies against ADP/ATP carrier from dilated cardiomyopathy

Abstract

Am Heart J

J Am Coll Cardiol

Clin Immunol Immunopathol

Clin Immunol Immunopathol

Clin Immunol Immunopathol

Lancet

Am J Cardiol

Clin Immunol Immunopathol

The pathogenesis of dilated cardiomyopathy: current progress

G Ital Cardiol

Myocarditis and dilated cardiomyopathy

Annu Rev Med

Heart specific autoantibodies induced by coxsackievirus B3: identification of heart autoantigens

Clin Immunol Immunopathol

Detection of coxsackie B virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy

Lancet

End-stage dilated cardiomyopathy persistence of enterovirus RNA in myocardium at cardiac transplantation and lack of immune response

Circulation

Immunological analysis of autoantibodies against the adenine nucleotide translocator in dilated cardiomyopathy

J Mol Cell Cardiol

Anti-mitochondrial antibodies (anti-M7) in heart disease recognize epitopes of bacterial and mammalian sarcosine dehydrogenase

Clin Exp Immunol

Identification of α- and β-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy

Circulation

Autoantibodies against beta-adrenoceptors in human idiopathic dilated cardiomyopathy

Circ Res

Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy

J Clin Invest

Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy

J Clin Invest

The ADP/ATP carrier as a mitochondrial auto-antigen: facts and perspective

Ann New York Acad Sci

The significance of autoantibodies against the ADP/ATP carrier for the pathogenesis of myocarditis and dilated cardiomyopathy: clinical and experimental data