Jahns R, Boivin V, Krapf T, Wallukat G, Boege F, Lohse M J
Department of Internal Medicine, Medizinische Poliklinik, University of Wuerzburg, Germany.
J Am Coll Cardiol. 2000 Oct;36(4):1280-7. doi: 10.1016/s0735-1097(00)00881-0.
Our study attempted to gain further understanding of the allosteric effects of human autoantibodies on beta1-adrenergic receptor (beta1-AR) function.
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.
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.
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).
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.
我们的研究试图进一步了解人类自身抗体对β1 - 肾上腺素能受体（β1 - AR）功能的变构效应。
最近，我们报道了扩张型心肌病（DCM，患病率26%）或缺血性心肌病（ICM，患病率10%）患者中存在激活型抗β1 - AR抗体；然而，它们的功能效应尚未得到充分表征。
在本研究中，我们在30例DCM患者中的8例中检测到了功能活跃的受体抗体。使用合成受体肽和完整的重组人β1 - AR对其免疫学和功能特性进行了分析，并与在兔和小鼠中产生的针对选定β1 - AR结构域的异源抗体进行了比较。
针对第二个细胞外结构域的兔、小鼠和人抗β1 - AR优先结合天然受体构象，并损害放射性配体与受体的结合。然而，它们的功能效应有很大差异：兔和小鼠抗体降低基础和激动剂刺激的cAMP产生，而患者抗体（n = 8）增加基础cAMP产生，其中6例还增加激动剂刺激的受体活性（即作为受体敏化剂）。8例人抗β1 - AR中有2例增加基础受体活性但降低激动剂刺激的受体活性（即作为部分激动剂）。
针对相同小β1 - AR结构域的抗体可具有非常不同的变构效应，范围从抑制到激动剂促进活性。激活型自身抗体与严重心脏功能障碍相关，因此可能参与人类心肌病的发生和/或病程。
