Key result
Human autoantibodies against the beta1-adrenergic receptor from DCM patients increased basal receptor activity, acting as receptor-sensitizing agents or partial agonists.
Why the study?
Activating anti-beta1-AR antibodies exist in DCM and ICM, but their functional effects had not been thoroughly characterized.
Observational (n=30)
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“IgGs with agonist activity for the β1-adrenergic receptor have been found in sera not only from patients with Chagas disease, but also from patients with idiopathic dilated cardiomyopathy as well as ischemic cardiomyopathy. Whether these antibodies merely correlate with myocardial inflammation that leads to CHF, result from myocardial inflammation, or actually contribute to the pathogenesis of CHF could not be ascertained”
“The prevalence of anti-β1AR Abs in patients with DCM ranges from 26% to 60%, and the presence of these autoantibodies correlates with a poor prognosis”
“Autoantibodies to β1AR have been detected in some patients with DCM and have been associated with increased mortality. Mechanistically, these antibodies appear to stimulate the β1AR and promote cardiac myocyte apoptosis through cyclic adenosine monophosphate–mediated signaling of caspase-dependent pathways and calcium overload”
Autoantibody modulation of beta1-receptors may improve EF in HF; leaves open viability as a therapeutic target pending validation.
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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Jahns et al. (2000) conducted an observational in Dilated cardiomyopathy (n=30). Human anti-beta1-adrenergic receptor autoantibodies vs. Rabbit and mouse heterologous antibodies was evaluated on Modulation of beta1-adrenoceptor activity (cAMP production). Human autoantibodies against the beta1-adrenergic receptor from DCM patients increased basal receptor activity, acting as receptor-sensitizing agents or partial agonists.
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