Abstract
OBJECTIVES: Our study attempted to gain further understanding of the
allosteric effects of human autoantibodies on beta1-adrenergic receptor
(beta1-AR) function. BACKGROUND: Recently, we reported on the existence
of activating anti-beta1-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 beta1-AR, and were compared with those of heterologous antibodies
to selected beta1-AR domains generated in rabbits and mice. RESULTS:
Rabbit, mouse, and human anti-beta1-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-beta1-AR increased basal but
decreased agonist-stimulated receptor activity (i.e., acted as partial
agonists). CONCLUSIONS: Antibodies against the same small beta1-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.
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