An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis
An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis
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DOI：
10.1093/eurheartj/ehy567
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发表时间：
2018-11-21
影响因子：
39.3
通讯作者：
Hamilton, Robert M.
中科院分区：
文献类型：
--
作者：
Chatterjee, Diptendu;Fatah, Meena;Hamilton, Robert M.
致心律失常性右室心肌病（ARVC）以右室心肌替代和危及生命的室性心律失常为特征。桥粒基因突变有时被确定，但临床和遗传诊断仍然具有挑战性。桥粒皮肤病可由桥粒基因突变或自身抗体引起。我们试图确定是否存在抗桥粒抗体与ARVC.Methods和结果的主题，我们评估了ARVC主题和控制心脏桥粒钙粘蛋白的抗体。将蛋白质印迹上的桥粒芯糖蛋白-2（DSG 2）、桥粒芯胶蛋白-2和N-钙粘蛋白暴露于受试者和对照的初级和验证队列以及天然存在的ARVC拳击犬模型中的血清。我们在12/12和25/25个明确的ARVC队列和7/8个边缘受试者中鉴定出抗DSG 2抗体。在两个对照组中，11/12例不存在抗体，1/12例微弱，20/20例不存在抗体。抗DSG 2抗体存在于10/10只患有ARVC的Boxer犬中，而在18/18只未患有ARVC的Boxer犬中不存在。在人类中，抗DSG 2抗体的水平与室性早搏的负担相关（r = 0.70），并且抗体在体外引起间隙连接功能障碍，这是ARVC的共同特征。抗DSG 2抗体存在于ARVC受试者中，无论是否鉴定出潜在突变或存在哪种突变。结论抗DSG 2抗体是ARVC敏感、特异的生物标志物。靶相关突变导致的自身免疫的发展是独特的。抗DSG 2抗体可能解释了在ARVC中经常发现的心脏炎症，并可能代表一种新的治疗靶点。
Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC.Methods and results We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified antiDSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified.Conclusion Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.