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
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.
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