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

J Am Coll Cardiol. 2000 Oct;36(4):1280-7. doi: 10.1016/s0735-1097(00)00881-0.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Autoantibodies / pharmacology*
  • Biomarkers / blood
  • Blotting, Western
  • Cyclic AMP / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Heart Failure / immunology*
  • Heart Failure / metabolism
  • Humans
  • Immunodominant Epitopes / immunology
  • Immunodominant Epitopes / metabolism
  • Immunoglobulin G / immunology
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Middle Aged
  • Rabbits
  • Receptors, Adrenergic, beta-1 / drug effects
  • Receptors, Adrenergic, beta-1 / immunology
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Recombinant Proteins
  • Signal Transduction / drug effects

Substances

  • Autoantibodies
  • Biomarkers
  • Immunodominant Epitopes
  • Immunoglobulin G
  • Receptors, Adrenergic, beta-1
  • Recombinant Proteins
  • Cyclic AMP