Keppeke Gerson Dierley, Calise S John, Chan Edward K L, Andrade Luis Eduardo C
Gerson Dierley Keppeke, Luis Eduardo C Andrade, Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP 04023-062, Brazil.
World J Gastroenterol. 2016 Feb 14;22(6):1966-74. doi: 10.3748/wjg.v22.i6.1966.
Chronic inflammation associated with hepatitis C virus (HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α (IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies (ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings (RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings (anti-RR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.
丙型肝炎病毒（HCV）感染相关的慢性炎症可导致致残性肝脏疾病，并进展为肝硬化和肝细胞癌。尽管最近有了更有效且毒性更小的治疗选择，但在世界大部分地区，标准治疗仍包括每周注射一次聚乙二醇化干扰素α（IFN-α）以及每日服用利巴韦林。HCV患者经常出现循环中的非器官特异性自身抗体，在抗核抗体（ANA）间接免疫荧光检测中表现出多种染色模式。接受IFN-α和利巴韦林治疗的HCV患者中，20%至40%会产生自身抗体，呈现出一种特殊的ANA模式，其特征为杆状和环状（RR）结构。本文旨在综述近期关于HCV患者在IFN-α/利巴韦林治疗后RR结构和抗杆状/环状（抗RR）自身抗体产生的报道。抗RR自身抗体在治疗约六个月时首次出现，并在十二个月左右达到高峰。治疗结束后，一半患者的抗RR滴度下降/消失，另一半患者则保持稳定。一些研究观察到复发患者（即最初治疗成功后循环病毒再次出现的患者）中抗RR抗体的频率更高。HCV患者中抗RR自身抗体的主要靶标是肌苷-5'-单磷酸脱氢酶2（IMPDH2），它是鸟苷三磷酸生物合成途径中的限速酶。利巴韦林是一种直接的IMPDH2抑制剂，能够在体外和体内诱导RR结构的形成。总之，这些观察结果导致了这样一种假设，即抗RR自身抗体的产生是免疫耐受破坏的一种人类模型，使我们能够从假定的触发事件开始探索体液自身免疫反应：接触利巴韦林和干扰素。
