%0 Journal Article %1 Jahns2000 %A Jahns, R. %A Boivin, V. %A Krapf, T. %A Wallukat, G. %A Boege, F. %A Lohse, M. J. %D 2000 %J J Am Coll Cardiol %K AMP/metabolism Aged Animals Assay Autoantibodies/immunology/*pharmacology Biological Blotting, Cyclic Enzyme-Linked Epitopes/immunology/metabolism Failure/*immunology/metabolism Female G/immunology Heart Humans Immunodominant Immunoglobulin Immunosorbent Male Markers/blood Membrane Mice Middle Potentials/drug Proteins Rabbits Recombinant Signal Transduction/drug Western beta-1/drug effects effects/immunology/*metabolism Receptor Adrenergic %N 4 %P 1280-7 %T Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11028484 %V 36 %X 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.

@article{Jahns2000, 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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Jahns, R. and Boivin, V. and Krapf, T. and Wallukat, G. and Boege, F. and Lohse, M. J.}, biburl = {https://www.bibsonomy.org/bibtex/2c55b30654bd4e85f026d91ed3dead837/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {624ecaaaad10ab6f31a44b7bb1edebe4}, intrahash = {c55b30654bd4e85f026d91ed3dead837}, issn = {0735-1097 (Print) 0735-1097 (Linking)}, journal = {J Am Coll Cardiol}, keywords = {AMP/metabolism Aged Animals Assay Autoantibodies/immunology/*pharmacology Biological Blotting, Cyclic Enzyme-Linked Epitopes/immunology/metabolism Failure/*immunology/metabolism Female G/immunology Heart Humans Immunodominant Immunoglobulin Immunosorbent Male Markers/blood Membrane Mice Middle Potentials/drug Proteins Rabbits Recombinant Signal Transduction/drug Western beta-1/drug effects effects/immunology/*metabolism Receptor Adrenergic}, month = Oct, note = {Jahns, R Boivin, V Krapf, T Wallukat, G Boege, F Lohse, M J Comparative Study Research Support, Non-U.S. Gov't United states Journal of the American College of Cardiology J Am Coll Cardiol. 2000 Oct;36(4):1280-7.}, number = 4, pages = {1280-7}, shorttitle = {Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies}, timestamp = {2010-12-14T18:22:40.000+0100}, title = {Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11028484}, volume = 36, year = 2000 }