HCV Infection Enhances Th17 Commitment, Which Could Affect the Pathogenesis of Autoimmune Diseases Yasuteru Kondo 1 *, Masashi Ninomiya 1 , Osamu Kimura 1 , Keigo Machida 2 , Ryo Funayama 3 , Takeshi Nagashima 3 , Koju Kobayashi 1 , Eiji Kakazu 1 , Takanobu Kato 4 , Keiko Nakayama 3 , Michael M. C. Lai 2,5 , Tooru Shimosegawa 1 1 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai City, Miyagi, Japan, 2 Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America, 3 Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai City, Miyagi, Japan, 4 Department of Virology II, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan, 5 China Medical University, Taichung, Taiwan Abstract Background: 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. Methods: Therefore, we analyzed the relationship between persistent infection of HCV and the mechanism of Th17 cell induction ex vivo and in vitro. Results: 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-b 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-b, 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 IL1b, IL23, IL6 and TGF-b 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 RORct as a Th17 master gene. Conclusion: Infection by lymphotropic HCV might enhance the Th17 development and contribute to understanding the pathogenesis of autoimmune-related diseases. Citation: Kondo Y, Ninomiya M, Kimura O, Machida K, Funayama R, et al. (2014) HCV Infection Enhances Th17 Commitment, Which Could Affect the Pathogenesis of Autoimmune Diseases. PLoS ONE 9(6): e98521. doi:10.1371/journal.pone.0098521 Editor: Stephen J. Polyak, University of Washington, United States of America Received February 20, 2014; Accepted May 2, 2014; Published June 6, 2014 Copyright: ß 2014 Kondo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported in part by Grant-in Aid from the Ministry of Education, Culture, Sport, Science, and Technology of Japan (Y.K. #21790642, #23790761 and #25460970), Grant from the Japan Society of Hepatology (Y.K), the National Institute on Alcohol Abuse and Alcoholism (K.M. #R01 AA018857) and the American Cancer Society (K.M. #RSG-12-177-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: yasuteru@ebony.plala.or.jp Introduction Cellular and humoral immune responses to HCV play an important role in the pathogenesis of chronic hepatitis, HCC and B-lymphocyte proliferative disorders including mixed cryoglobu- linemia, a disorder characterized by the oligoclonal proliferation of B cells [1–5]. B cell activation and/or dis-regulation could originate as a result of HCV binding to CD81 tetraspanin molecule or as a consequence of its ability to replicate in B lymphocytes[6]. It has been reported that HCV could infect B lymphocytes[7–9]. We previously reported that HCV-replication in B lymphocytes could induce immunoglobulin hypermutation and reduce the affinity and neutralizing activities of antibodies against HCV envelope protein[5]. On the other hand, the hypermutation of immunoglobulin might induce autoantibodies that contribute to the immunopathogenesis of autoimmune diseases, since various kinds of autoimmune diseases were reported to have a significant relationship with persistent HCV infection [10–12]. Previously, our group reported that the existence of HCV in T lymphocytes could affect the development and proliferation of type 1 T helper (Th1) cells[3,4,13]. Other groups have also reported the existence of HCV in T lymphocytes[14,15]. HCV replication in T lymphocytes could suppress Interferon-c (IFN-c)/signal transducers and activators of transcription factor 1 (STAT-1) signaling that might affect signal transducers and activators of transcription factor 3 (STAT-3) signaling[4,13]. PLOS ONE | www.plosone.org 1 June 2014 | Volume 9 | Issue 6 | e98521