Direct evidence for a β1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy
Direct evidence for a β1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy
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DOI：
10.1172/jci200420149
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发表时间：
2004-05-01
影响因子：
15.9
通讯作者：
Lohse, MJ
中科院分区：
文献类型：
--
作者：
Jahns, R;Boivin, V;Lohse, MJ
今天，扩张型心肌病（DCM）是年轻人严重心力衰竭和残疾的主要原因，因此是公共卫生的一个挑战。大约30%的DCM病例是遗传性的;然而，绝大多数病例是散发性的，并且怀疑是病毒或免疫发病机制。根据自身免疫性疾病发病机制的既定假设，在这里，我们提供了直接的证据表明，针对心脏β（1）-肾上腺素能受体的自身免疫攻击可能在DCM中发挥因果作用。首先，我们每月免疫近交系大鼠对抗第二胞外Pi受体环（β（1）-ECII;人与大鼠之间100%序列同一性）。所有这些大鼠首先出现受体刺激性抗β（1）-ECII抗体，然后在9个月后出现进行性严重左心室扩张和功能障碍。第二，我们每月将抗β（1）-ECII阳性和Ab阴性动物的血清转移到同一品系的健康大鼠中。引人注目的是，所有抗β（1）-ECII转移的大鼠也在相似的时间范围内出现了相似的心肌病表型，这强调了这些受体Ab的致病潜力。因此，β 1-肾上腺素能受体靶向的自身免疫性DCM现在应该与其他已知的受体Ab介导的自身免疫性疾病，如格雷夫斯病或重症肌无力分类。虽然在实验动物模型中进行，但我们的发现应进一步鼓励开发治疗策略，以对抗受体Ab阳性DCM患者中有害的抗β（1）-ECII。
Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults and thus is a challenge for public health. About 30% of DCM cases are genetic in origin; however, the large majority of cases are sporadic, and a viral or immune pathogenesis is suspected. Following the established postulates for pathogenesis of autoimmune diseases, here we provide direct evidence that an autoimmune attack directed against the cardiac beta(1)-adrenergic receptor may play a causal role in DCM. First, we immunized inbred rats against the second extracellular Pi-receptor loop (beta(1)-ECII; 100% sequence identity between human and rat) every month. All these rats developed first, receptor-stimulating anti-beta(1)-ECII Ab's and then, after 9 months, progressive severe left ventricular dilatation and dysfunction. Second, we transferred sera from anti-beta(1)-ECII-positive and Ab-negative animals every month to healthy rats of the same strain. Strikingly, all anti-beta(1)-ECII-transferred rats also developed a similar cardiomyopathic phenotype within a similar time frame, underlining the pathogenic potential of these receptor Ab's. As a consequence, Pi-adrenergic receptor-targeted autoimmune DCM should now be categorized with other known receptor Ab-mediated autoimmune diseases, such as Graves disease or myasthenia gravis. Although carried out in an experimental animal model, our findings should further encourage the development of therapeutic strategies that combat harmful anti-beta(1)-ECII in receptor Ab-positive DCM patients.