Targeting receptor antibodies in immune cardiomyopathy.
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 beta1-adrenergic receptor (beta1-aabs) have been assigned a pivotal role in the pathogenesis of immune cardiomyopathy. Conformational beta1-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 beta1-(auto)antibody-induced damage.
Jahns
Roland
R
Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, Germany. jahns_r@klinik.uni-wuerzburg.de
Schlipp
Angela
A
Boivin
Valérie
V
Lohse
Martin J
MJ
D001323:Autoantibodies / Q000187:drug effects*; D015551:Autoimmunity / Q000187:drug effects; D009202:Cardiomyopathies / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology*
D001323:Autoantibodies; D018342:Receptors, Adrenergic, beta-1