Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies.
OBJECTIVE
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.
Jahns
R
R
Department of Internal Medicine, Medizinische Poliklinik, University of Wuerzburg, Germany. Jahns@wpxx02.toxi.uni-wuerzburg.de
Boivin
V
V
Krapf
T
T
Wallukat
G
G
Boege
F
F
Lohse
M J
MJ
D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006333:Heart Failure / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D011817:Rabbits; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects
D001323:Autoantibodies; D015415:Biomarkers; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D018342:Receptors, Adrenergic, beta-1; D011994:Recombinant Proteins; D000242:Cyclic AMP