Modulation of beta1-adrenoceptor activity by domain-specific antibodies and-heart failure-associated autoantibodies

OBJECTIVES Our study attempted to gain further understanding of the allosteric effects of human autoantibodies on beta(1)-adrenergic receptor (beta(1)-AR) function. BACKGROUND Recently, we reported on the existence of activating anti-beta(1)-AR antibodies in patients with dilated cardiomyopathy (DCM 26% prevalence) or ischemic cardiomyopathy (ICM, 10% prevalence); however, their functional effects have not yet been thoroughly characterized. METHODS In this study we detected functionally active receptor-antibodies in 8 out of 30 DCM patients. Their immunological and functional properties were analyzed using both synthetic receptor-peptides and intact recombinant human beta(1)-AR, and were compared with those of heterologous antibodies to selected beta(1)-AR domains generated in rabbits and mice. RESULTS Rabbit, mouse, and human anti-beta(1)-AR against the second extracellular domain preferentially bound to a native receptor conformation and impaired radioligand binding to the receptor. However, their functional effects differed considerably: Rabbit and mouse antibodies decreased both basal and agonist-stimulated cAMP production, whereas the patient antibodies (n = 8) increased basal, and six of them also increased agonist-stimulated receptor activity (i.e., acted as receptor-sensitizing agents). Two out of eight human anti-beta(1)-AR increased basal but decreased agonist-stimulated receptor activity (i.e., acted as partial agonists). CONCLUSIONS Antibodies against the same small beta(1)-AR domain can have very divergent allosteric effects, ranging from inhibitory to agonist-promoting activities. Activating autoantibodies were associated with severe cardiac dysfunction and thus might be involved in the development and/or course of human cardiomyopathy. (J Am Coll Cardiol 2000;36:1280-7) (C) 2000 by the American College of Cardiology.