PhIP-Seq Reveals Autoantibodies for Ubiquitously Expressed Antigens in Viral Myocarditis.
PhIP-Seq Reveals Autoantibodies for Ubiquitously Expressed Antigens in Viral Myocarditis.
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心肌炎是心肌的炎症，病毒感染是这种疾病的常见原因。一些患者的心肌炎可进展为扩张型心肌病（DCM）。柯萨奇病毒B3（CVB 3）的小鼠模型通常用于了解DCM患者的疾病进展。在本文中，我们试图分析抗体的心脏抗原，可能会产生的心脏损伤的结果，在动物感染CVB 3使用一种技术称为噬菌体免疫沉淀测序（PhIP-Seq）。这些分析使我们确定了几种蛋白质的抗体，这些蛋白质以前没有报道过，可能与人类疾病有关。肠道病毒如B组柯萨奇病毒（CVB）通常被怀疑是可导致扩张型心肌病（DCM）的心肌炎的原因，并且CVB 3心肌炎的小鼠模型常规用于理解DCM发病机制。从机制上讲，由于选择抗原的自身抗体的存在，怀疑自身免疫。然而，它们的作用仍然是神秘的，这也提出了一个问题，即自身抗体的广度是否得到了充分的表征。在这里，我们试图全面分析自身抗体库使用噬菌体免疫沉淀测序（PhIP-Seq），一个通用的和高通量的平台，在小鼠模型中的CVB 3心肌炎。首先，使用VirScan文库的PhIP-Seq分析揭示了感染组中仅对CVB 3具有抗体反应性，而对照组中没有，从而验证了该模型中的技术。第二，使用小鼠肽库，我们检测到来自感染动物中的25种蛋白质的32种肽的自身抗体，这些蛋白质普遍表达，并且以前没有报道过。第三，通过使用ELISA作为二次检测，我们证实了CVB 3感染动物血清中对细胞色素c氧化酶组装因子4同源物（COA 4）和磷酸肌醇-3-激酶接头蛋白1（PIK 3AP 1）的抗体反应性，表明通过PhIP-Seq技术检测抗体的特异性。第四，我们注意到CVB 3和CVB 4感染中相似的抗体反应模式，表明COA 4和PIK 3AP 1反应性抗体可能是多种CVB感染所共有的。用流感感染动物证实了自身抗体的特异性，这些动物对任何检测抗原均无反应性。综上所述，我们的数据表明，通过PhIP-Seq鉴定的自身抗体可能与CVB发病机制相关，在人类DCM患者中可能预期类似的反应性。
Myocarditis is the inflammation of the heart muscle, and viral infections are a common cause of this disease. Myocarditis in some patients can progress to dilated cardiomyopathy (DCM). The mouse model of coxsackievirus B3 (CVB3) is commonly used to understand this disease progression in DCM patients. In this paper, we have attempted to analyze antibodies for heart antigens that could be produced as a result of heart damage in animals infected with CVB3 using a technique called Phage ImmunoPrecipitation Sequencing (PhIP-Seq). The analyses led us to identify antibodies for several proteins that were not previously reported that may have relevance to human disease. Enteroviruses such as group B coxsackieviruses (CVB) are commonly suspected as causes of myocarditis that can lead to dilated cardiomyopathy (DCM), and the mouse model of CVB3 myocarditis is routinely used to understand DCM pathogenesis. Mechanistically, autoimmunity is suspected due to the presence of autoantibodies for select antigens. However, their role continues to be enigmatic, which also raises the question of whether the breadth of autoantibodies is sufficiently characterized. Here, we attempted to comprehensively analyze the autoantibody repertoire using Phage ImmunoPrecipitation Sequencing (PhIP-Seq), a versatile and high-throughput platform, in the mouse model of CVB3 myocarditis. First, PhIP-Seq analysis using the VirScan library revealed antibody reactivity only to CVB3 in the infected group but not in controls, thus validating the technique in this model. Second, using the mouse peptide library, we detected autoantibodies to 32 peptides from 25 proteins in infected animals that are ubiquitously expressed and have not been previously reported. Third, by using ELISA as a secondary assay, we confirmed antibody reactivity in sera from CVB3-infected animals to cytochrome c oxidase assembly factor 4 homolog (COA4) and phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1), indicating the specificity of antibody detection by PhIP-Seq technology. Fourth, we noted similar antibody reactivity patterns in CVB3 and CVB4 infections, suggesting that the COA4- and PIK3AP1-reactive antibodies could be common to multiple CVB infections. The specificity of the autoantibodies was affirmed with influenza-infected animals that showed no reactivity to any of the antigens tested. Taken together, our data suggest that the autoantibodies identified by PhIP-Seq may have relevance to CVB pathogenesis, with a possibility that similar reactivity could be expected in human DCM patients.
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影响因子：
32.4
作者：
Angkeow, Julia W.;Monaco, Daniel R.;Chen, Athena;Venkataraman, Thiagarajan;Jayaraman, Sahana;Valencia, Cristian;Sie, Brandon M.;Liechti, Thomas;Farhadi, Payam N.;Funez-dePagnier, Gabriela;Sherman-Baust, Cheryl A.;Wong, May Q.;Ruczinski, Ingo;Caturegli, Patrizio;Sears, Cynthia L.;Simner, Patricia J.;Round, June L.;Duggal, Priya;Laserson, Uri;Steiner, Theodore S.;Sen, Ranjan;Lloyd, Thomas E.;Roederer, Mario;Mammen, Andrew L.;Longman, Randy S.;Rider, Lisa G.;Larman, H. Benjamin
通讯作者：
Larman, H. Benjamin
影响因子：
16.6
作者：
Bullard BL;Corder BN;DeBeauchamp J;Rubrum A;Korber B;Webby RJ;Weaver EA
通讯作者：
Weaver EA
影响因子：
7.8
作者：
Corder, Brigette N.;Bullard, Brianna L.;Weaver, Eric A.
通讯作者：
Weaver, Eric A.
影响因子：
15.9
作者：
Helft, Julie;Manicassamy, Balaji;Merad, Miriam
通讯作者：
Merad, Miriam
影响因子：
64.5
作者：
Gruber, Conor N.;Patel, Roosheel S.;Bogunovic, Dusan
通讯作者：
Bogunovic, Dusan