Kondo Yasuteru, Ninomiya Masashi, Kimura Osamu, Machida Keigo, Funayama Ryo, Nagashima Takeshi, Kobayashi Koju, Kakazu Eiji, Kato Takanobu, Nakayama Keiko, Lai Michael M C, Shimosegawa Tooru
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai City, Miyagi, Japan.
Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2014 Jun 6;9(6):e98521. doi: 10.1371/journal.pone.0098521. eCollection 2014.
Various kinds of autoimmune diseases have been reported to have a significant relationship with persistent hepatitis c virus (HCV) infection and Th17 cells. Previously, our group reported that the existence of HCV in T lymphocytes could affect the development of CD4+ helper T cells and their proliferation, in addition to the induction of immunoglobulin hyper-mutation.
Therefore, we analyzed the relationship between persistent infection of HCV and the mechanism of Th17 cell induction ex vivo and in vitro.
The prevalence of autoimmune-related diseases in chronic hepatitis c patients (CH-C) was significantly higher than in other types of chronic hepatitis (hepatitis B and NASH). A significantly higher frequency of IL6 and TGF-β double-high patients was detected in CH-C than in other liver diseases. Moreover, these double-high patients had significantly higher positivity of anti-nuclear antibody, cryoglobulinemia, and lymphotropic HCV and higher amounts of IL1-β, IL21, IL23. In addition to the previously reported lymphotropic SB-HCV strain, we found a novel, genotype 1b lymphotropic HCV (Ly-HCV), by deep sequencing analysis. Lymphotropic-HCV replication could be detected in the lymphoid cells with various kinds of cytokine-conditions including IL1β, IL23, IL6 and TGF-β in vitro. Infection by HCV could significantly enhance the development of Th17 cells. The HCV protein responsible for inducing the Th17 cells was HCV-Core protein, which could enhance the STAT-3 signaling and up-regulate the expression of RORγt as a Th17 master gene.
Infection by lymphotropic HCV might enhance the Th17 development and contribute to understanding the pathogenesis of autoimmune-related diseases.
据报道，多种自身免疫性疾病与丙型肝炎病毒（HCV）持续感染及Th17细胞存在显著关联。此前，我们团队报道，T淋巴细胞中HCV的存在除了诱导免疫球蛋白超突变外，还会影响CD4+辅助性T细胞的发育及其增殖。
因此，我们分析了HCV持续感染与体外和体内Th17细胞诱导机制之间的关系。
慢性丙型肝炎患者（CH-C）中自身免疫相关疾病的患病率显著高于其他类型的慢性肝炎（乙型肝炎和非酒精性脂肪性肝炎）。与其他肝脏疾病相比，CH-C患者中IL6和TGF-β双高患者的比例显著更高。此外，这些双高患者的抗核抗体、冷球蛋白血症和嗜淋巴细胞性HCV阳性率显著更高，且IL1-β、IL21、IL23水平更高。除了先前报道的嗜淋巴细胞性SB-HCV毒株外，通过深度测序分析，我们还发现了一种新的1b基因型嗜淋巴细胞性HCV（Ly-HCV）。在包括IL1β、IL23、IL6和TGF-β在内的各种细胞因子条件下，体外可在淋巴细胞中检测到嗜淋巴细胞性HCV复制。HCV感染可显著促进Th17细胞的发育。诱导Th17细胞的HCV蛋白是HCV核心蛋白，它可增强STAT-3信号传导并上调Th17主基因RORγt的表达。
嗜淋巴细胞性HCV感染可能会促进Th17细胞的发育，并有助于理解自身免疫相关疾病的发病机制。
