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

Item Type:	Article
Title:	Modulation of beta1 adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies
Creators Name:	Jahns, R. and Boivin, V. and Krapf, T. and Wallukat, G. and Boege, F. and Lohse, M.J.
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.
Keywords:	Autoantibodies, Beta-1 Adrenergic Receptors, Biological Markers, Congestive Heart Failure, Cyclic AMP, Enzyme-Linked Immunosorbent Assay, Immunodominant Epitopes, Immunoglobulin G, Membrane Potentials, Recombinant Proteins, Signal Transduction, Western Blotting, Animals, Mice, Rabbits
Source:	Journal of the American College of Cardiology
ISSN:	0735-1097
Publisher:	Elsevier
Volume:	36
Number:	4
Page Range:	1280-1287
Date:	1 October 2000
Official Publication:	https://doi.org/10.1016/S0735-1097(00)00881-0
PubMed:	View item in PubMed

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