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J Am Coll Cardiol, 2000; 36:1280-1287
© 2000 by the American College of Cardiology Foundation
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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* {dagger}, Valérie Boivin, PhD{dagger}, Thorsten Krapf, MD{dagger}, Gerd Wallukat, MD{ddagger}, Fritz Boege, MD* and Martin J. Lohse, MD{dagger}

* Department of Internal Medicine, Medizinische Poliklinik, University of Wuerzburg, Wuerzburg, Germany
{dagger} Institute of Pharmacology, University of Wuerzburg, Wuerzburg, Germany
{ddagger} 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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