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CLINICAL STUDY: HEART FAILURE

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

Roland Jahns, MD^* , Valérie Boivin, PhD, Thorsten Krapf, MD, Gerd Wallukat, MD, Fritz Boege, MD^* and Martin J. Lohse, MD

^* Department of Internal Medicine, Medizinische Poliklinik, University of Wuerzburg, Wuerzburg, Germany
Institute of Pharmacology, University of Wuerzburg, Wuerzburg, Germany
Max Delbrück Center for Molecular Medicine, Berlin, Germany

Manuscript received December 13, 1999; revised manuscript received April 10, 2000, accepted June 13, 2000.

Reprint requests and correspondence: Dr. Roland Jahns, Medizinische Poliklinik, University of Wuerzburg, Klinikstrasse 6-8, D-97070 Wuerzburg, Germany
Jahns{at}wpxx02.toxi.uni-wuerzburg.de

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.

Abbreviations and Acronyms   anti-beta1-AR/-ECII = antibodies against the beta1-adrenergic receptor/second extracellular loop of the beta1-adrenergic receptor   beta1-AR = beta1-adrenergic receptor   beta-Me = beta-mercaptoethanol   BSA = bovine serum albumin   DCM = dilated cardiomyopathy   ELISA = enzyme-linked immunoassay   GST = glutathion-S-transferase   IBMX = isobutylmethylxanthine   PBS = phosphate buffered saline   SDS = sodium dodecyl sulfate

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