Targeting Receptor Antibodies in Immune Cardiomyopathy

ABSTRACT

Although autoimmunity represents a well-established pathogenetic principle in several endocrine (Graves' disease), rheumatic (systemic lupus erythematosus), and neurological disorders (myasthenia gravis, multiple sclerosis), this mechanism has only recently gained more attention in cardiac diseases. Depending on individual genetic predisposition, heart-directed autoimmune reactions are supposed to emerge as a consequence of cardiomyocyte injury induced by inflammation, ischemia, or exposure to cardiotoxic substances. Myocyte apoptosis or necrosis and subsequent liberation of a “critical amount” of cardiac autoantigens may then induce a self-directed immune response, which in the worst case results in perpetuation of autoantibody-mediated cardiac damage. In particular, functionally active autoantibodies (aabs) directed against the cardiac β1-adrenergic receptor (β1-aabs) have been assigned a pivotal role in the pathogenesis of immune cardiomyopathy. Conformational β1-aabs allosterically activate the sympathetic transmembrane signaling cascade, thereby increasing sarcoplasmatic cyclic adenosine monophosphate (cAMP) and calcium concentrations. Chronic cAMP production and calcium overload are cardiotoxic, leading to myocyte apoptosis, fibrotic repair, subsequent heart muscle dysfunction, and, finally, a dilative cardiomyopathic phenotype. Elimination by (extracorporeal) immunoadsorption or direct neutralization of the harmful receptor autoantibodies in the circulating blood represent promising strategies to protect the heart from β1-(auto)antibody-induced damage.

KEYWORDS

Antibody/Autoantibody - β-adrenergic receptor - idiopathic dilated cardiomyopathy - receptor peptides

REFERENCES

• 1 Lloyd-Jones D, Adams R, Carnethon M American Heart Association Statistics Committee and Stroke Statistics Subcommittee et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.  Circulation. 2009;  119(3) 480-486
• 2 Maron B J, Towbin J A, Thiene G et al.. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.  Circulation. 2006;  113(14) 1807-1816
• 3 Kindermann I, Kindermann M, Kandolf R et al.. Predictors of outcome in patients with suspected myocarditis.  Circulation. 2008;  118(6) 639-648
• 4 Kühl U, Pauschinger M, Seeberg B et al.. Viral persistence in the myocardium is associated with progressive cardiac dysfunction.  Circulation. 2005;  112(13) 1965-1970
• 5 Lang C, Sauter M, Szalay G et al.. Connective tissue growth factor: a crucial cytokine-mediating cardiac fibrosis in ongoing enterovirus myocarditis.  J Mol Med. 2008;  86(1) 49-60
• 6 Freedman N J, Lefkowitz R J. Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation.  J Clin Invest. 2004;  113(10) 1379-1382
• 7 Jahns R, Boivin V, Lohse M J. Beta(1)-adrenergic receptor function, autoimmunity, and pathogenesis of dilated cardiomyopathy.  Trends Cardiovasc Med. 2006;  16(1) 20-24
• 8 Limas C J. Autoimmunity in dilated cardiomyopathy and the major histocompatibility complex.  Int J Cardiol. 1996;  54(2) 113-116
• 9 Limas C J, Iakovis P, Anyfantakis A, Kroupis C, Cokkinos D V. Familial clustering of autoimmune diseases in patients with dilated cardiomyopathy.  Am J Cardiol. 2004;  93(9) 1189-1191
• 10 Luppi P, Rudert W A, Zanone M M et al.. Idiopathic dilated cardiomyopathy: a superantigen-driven autoimmune disease.  Circulation. 1998;  98(8) 777-785
• 11 Staudt A, Staudt Y, Dörr M et al.. Potential role of humoral immunity in cardiac dysfunction of patients suffering from dilated cardiomyopathy.  J Am Coll Cardiol. 2004;  44(4) 829-836
• 12 Göser S, Andrassy M, Buss S J et al.. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium.  Circulation. 2006;  114(16) 1693-1702
• 13 Caforio A L, Mahon N J, McKenna W J. Cardiac autoantibodies to myosin and other heart-specific autoantigens in myocarditis and dilated cardiomyopathy.  Autoimmunity. 2001;  34(3) 199-204
• 14 Fu M L. Anti-M2 muscarinic receptor autoantibodies and idiopathic dilated cardiomyopathy.  Int J Cardiol. 1996;  54(2) 127-135
• 15 Jahns R, Boivin V, Krapf T, Wallukat G, Boege F, Lohse M J. Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies.  J Am Coll Cardiol. 2000;  36(4) 1280-1287
• 16 Liang C S, Mao W, Liu J. Pro-apoptotic effects of anti-beta1-adrenergic receptor antibodies in cultured rat cardiomyocytes: actions on endoplasmic reticulum and the prosurvival PI3K-Akt pathway.  Autoimmunity. 2008;  41(6) 434-441
• 17 Lohse M J, Engelhardt S, Eschenhagen T. What is the role of beta-adrenergic signaling in heart failure?.  Circ Res. 2003;  93(10) 896-906
• 18 Jahns R, Boivin V, Hein L et al.. Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy.  J Clin Invest. 2004;  113(10) 1419-1429
• 19 Hoebeke J. Structural basis of autoimmunity against G protein coupled membrane receptors.  Int J Cardiol. 1996;  54(2) 103-111
• 20 Mobini R, Maschke H, Waagstein F. New insights into the pathogenesis of dilated cardiomyopathy: possible underlying autoimmune mechanisms and therapy.  Autoimmun Rev. 2004;  3(4) 277-284
• 21 Ferrari I, Levin M J, Wallukat G et al.. Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor.  J Exp Med. 1995;  182(1) 59-65
• 22 Smulski C, Labovsky V, Levy G, Hontebeyrie M, Hoebeke J, Levin M J. Structural basis of the cross-reaction between an antibody to the Trypanosoma cruzi ribosomal P2beta protein and the human beta1 adrenergic receptor.  FASEB J. 2006;  20(9) 1396-1406
• 23 Magnusson Y, Hjalmarson Å, Hoebeke J. Beta 1-adrenoceptor autoimmunity in cardiomyopathy.  Int J Cardiol. 1996;  54(2) 137-141
• 24 Rose N R. Infection, mimics, and autoimmune disease.  J Clin Invest. 2001;  107(8) 943-944
• 25 Caforio A L, Mahon N J, Tona F, McKenna W J. Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance.  Eur J Heart Fail. 2002;  4(4) 411-417
• 26 Eriksson U, Ricci R, Hunziker L et al.. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity.  Nat Med. 2003;  9(12) 1484-1490
• 27 Warne T, Serrano-Vega M J, Baker J G et al.. Structure of a beta1-adrenergic G-protein-coupled receptor.  Nature. 2008;  454(7203) 486-491
• 28 Kobilka B K, Schertler G FX. New G-protein-coupled receptor crystal structures: insights and limitations.  Trends Pharmacol Sci. 2008;  29(2) 79-83
• 29 Mao W, Fukuoka S, Iwai C et al.. Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine.  Am J Physiol Heart Circ Physiol. 2007;  293(3) H1636-H1645
• 30 Jahns R, Boivin V, Siegmund C, Inselmann G, Lohse M J, Boege F. Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure.  Circulation. 1999;  99(5) 649-654
• 31 Nikolaev V O, Boivin V, Störk S et al.. A novel fluorescence method for the rapid detection of functional beta1-adrenergic receptor autoantibodies in heart failure.  J Am Coll Cardiol. 2007;  50(5) 423-431
• 32 Beavo J A, Brunton L L. Cyclic nucleotide research—still expanding after half a century.  Nat Rev Mol Cell Biol. 2002;  3 710-718
• 33 Nikolaev V O, Bünemann M, Hein L, Hannawacker A, Lohse M J. Novel single chain cAMP sensors for receptor-induced signal propagation.  J Biol Chem. 2004;  279(36) 37215-37218
• 34 Nikolaev V O, Gambaryan S, Engelhardt S, Walter U, Lohse M J. Real-time monitoring of the PDE2 activity of live cells: hormone-stimulated cAMP hydrolysis is faster than hormone-stimulated cAMP synthesis.  J Biol Chem. 2005;  280(3) 1716-1719
• 35 Störk S, Boivin V, Horf R et al.. Stimulating autoantibodies directed against the cardiac beta1-adrenergic receptor predict increased mortality in idiopathic cardiomyopathy.  Am Heart J. 2006;  152(4) 697-704
• 36 Felix S B, Staudt A. Immunoadsorption as treatment option in dilated cardiomyopathy.  Autoimmunity. 2008;  41(6) 484-489
• 37 Müller I I, Klingel K, Nikolaev V O et al.. Immunoadsorption in a 40 year old man with dilated cardiomyopathy and underlying active myocarditis.  Clin Res Cardiol. 2008;  97 787-790
• 38 Anderton S M. Peptide-based immunotherapy of autoimmunity: a path of puzzles, paradoxes and possibilities.  Immunology. 2001;  104(4) 367-376
• 39 Neubert K, Meister S, Moser K et al.. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.  Nat Med. 2008;  14(7) 748-755