Imbalance of regulatory T cells and T helper type 17 cells in patients with chronic hepatitis C

Abstract

SummaryPegylated interferon and ribavirin combination therapy is known to be effective in suppressing viral replication in 50-60% of hepatitis C virus (HCV) -infected patients. However, HCV-infected patients often exhibit varied responses to therapy. Therefore, the identification of immunological markers associated with the clinical outcomes of antiviral treatment is critical for improvement of therapeutic options. In this study, we aimed to investigate the ratio of CD4 + CD25 + FoxP3 + regulatory T (Treg) cells to interleukin-17A (IL-17A) -producing T helper type 17 (Th17) cells, and its association with clinical outcomes in response to anti-HCV treatment. In all, 114 patients with HCV infection received pegylated interferon-a2a and ribavirin therapy for 48 weeks, and the frequency of Treg cells and Th17 cells as well as the levels of secreted cytokines were longitudinally analysed by flow cytometry and ELISA. Treg cell proportions and IL-10 production were significantly elevated in HCV-infected patients, especially for HCV genotype 1b. However, the frequency of Th17 cells as well as the secretion of IL-17, IL-22 and IL-23 did not reveal notable difference between HCV infections and healthy individuals. Inhibition of HCV replication was accompanied by a reduction in Treg cells, but little influence on Th17 cells, which led to a significant decrease in Treg : Th17 ratios. Skewed Treg : Th17 ratios existed in chronic hepatitis C. HCV RNA load is closely associated with Treg : Th17 ratios during pegylated interferona2a and ribavirin treatment in HCV-infected patients. The imbalance of Treg cells to Th17 cells might play an important role in persistent HCV infection.

Relative and combined Effects of Ethanol and Hepatitis C Virus Infection on Serum Interleukin-17 Levels

“…Although we did fi nd that HCV infection was accompanied by an increase in IL-17 levels, no association was found with viral load, in accordance with other authors [13,20]. Similarly, although IL-17 was also increased in alcoholics, we also failed to fi nd any association with daily ethanol intake or duration of alcoholism.…”

“…Hao, et al, also failed to fi nd differences between controls and 114 HCV -infected patients [20]. Therefore, a great deal of controversy exists regarding the role of Th17 cells in HCV infection.…”

Divergent effects of type-I interferons on regulatory T cells

“…Conversely, another group could not detect any change in Treg frequency or suppressive function at 8 or 24 weeks of therapy, or at 24 weeks at follow-up [56]. Wang et al could even observe a decline in Treg frequency, as identified as CD4+ CD25+ CD127low, at 9 months of therapy [57], a finding confirmed by Hao et al, who detected a drop in Treg proportions, estimated as CD4+ CD25+ FOXP3+, in rapid virological responder patients from 4 to 48 weeks of therapy [58]. In line with the latter studies, and with data in the mouse model of chronic LCMV infection [24], we have recently observed that Treg frequency significantly drops in the peripheral blood of CHC patients as early as at day 2 of IFN therapy, mostly in responder patients, suggesting that IFNs may acutely lead to a Treg decline which may be involved in the mounting of appropriate anti-viral responses (S.P., I.P., E.T., V.B.…”

Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C

“…IL-17A has been implicated in the host defense against microbial pathogens but is also associated with inflammatory disorders when produced in excess [30,41], and the cytokine levels were correlated with serum ALT levels or viral copy numbers in CHC patients [21,42]. However, IL-17A was not significantly elevated in CHC patients when compared to the healthy control group in other studies [28,43]. We observed significant elevation of IL-17A levels only in non-RVR patients infected with HCV genotype 1 (Fig 1).…”