Th17 cells enhance viral persistence

[stef2011]

this is extremely interesting because th17 is potently suppressed by high dose vit d, so suppressed to recover autoimmune diseases in 95% cases, and this may be one of the actions that vit d has on hbv and in general viruses

full paper
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646583/?report=classic

most interesting parts:
Abstract
Persistent viral infection and its associated chronic diseases are a global health concern. Interleukin (IL) 17–producing Th17 cells have been implicated in the pathogenesis of various autoimmune diseases, and in protection from bacterial or fungal infection. However, the role of Th17 cells in persistent viral infection remains unknown. We report that Th17 cells preferentially develop in vitro and in vivo in an IL-6–dependent manner after Theiler’s murine encephalomyelitis virus infection. Th17 cells promote persistent viral infection and induce the pathogenesis of chronic demyelinating disease. IL-17 up-regulates antiapoptotic molecules and, consequently, increases persistent infection by enhancing the survival of virus-infected cells and blocking target cell destruction by cytotoxic T cells. Neutralization of IL-17 augments virus clearance by eliminating virus-infected cells and boosting lytic function by cytotoxic T cells, leading to the prevention of disease development. Thus, these results indicate a novel pathogenic role of Th17 cells via IL-17 in persistent viral infection and its associated chronic inflammatory diseases.

[stef2011]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838538/

Abstract
Th17 cells, a class of CD4+ T cells, have been identified as novel effector cells, which play a pivotal role in several inflammatory and autoimmune diseases. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has emerged as a direct regulator of immune system function in humans. Accumulating reports demonstrated that 1,25(OH)2D3 possessed anti-inflammatory activity on Th17 cells to maintain immunologic homeostasis. This report will review the novel immune regulatory role of 1,25(OH)2D3 in its potential use for Th17 cell-related inflammatory and autoimmune conditions.

[stef2011]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404917/

Changes of Treg and Th17 cells balance in the development of acute and chronic hepatitis B virus infection
Liang Xue-Song,corresponding author1 Li Cheng-Zhong,1 Zhou Ying,2 and Wan Mo-Bincorresponding author1
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract
Background

Many studies suggest that in chronic hepatitis B virus (HBV) infection regulate T (Treg) cells and interlukin-17-producing T help cells (Th17) are mutually antagonistic in the immune response. This study is aimed to reveal the cell differentiation environment and the significance of Treg and Th17 balance in the development of acute and chronic HBV infection.

Methods

Ten patients with acute HBV infection (AHB) and forty-eight patients with chronic HBV infection, including 12 asymptomatic HBV carriers (HBV carriers), 18 chronic hepatitis B patients (CHB) and 18 acute-on-chronic HBV-related liver failure (ACHBLF) were enrolled. Treg and Th17 cells differentiation related cytokine levels were detected by using ELISA. Flow cytometry was employed to count the Treg and Th17 frequency in peripheral blood.

Results

Compared to health controls both AHB and ACHBLF patients favoured Th17 cell differentiation, accompanied by a higher proportion of peripheral Th17 cells (P < 0.01) and high level of interleukin-17A (IL-17A) (P < 0.01). However, asymptomatic HBV carriers and CHB were conducive to Treg cell differentiation. In AHB and ACHBLF, peripheral blood IL-17A + CD4 + T cell frequency increased significantly compared with healthy controls. Changes of Treg and Th17 cell frequency were not completely consistent. Both CHB and ACHBLF had lower level of Treg/Th17 ratio than in health control (P < 0.05). Both plasm IL-17A levels (r = −0.72, p<0.001) and Th17 frequency(r = −0.49, p = 0.0003) negatively correlated with plasma HBV DNA load in patients with chronic HBV infection. In addition, both Th17 frequency and plasm IL-17A levels positively correlated with ALT (r = 0.33,p = 0.01 Vs r = 0.29,p = 0.04) and total bilirubin levels (r = 0.72,p<0.0001 Vs r = 0.53,p = 0.0001) in these chronic HBV-infected subjects. However, for AHB there were positive correlation between both Th17 frequency (r = 0.64, p = 0.04) and plasm IL-17A levels (r = 0.69, p = 0.02) with serum ALT levels, but no significant correlation between both HBV DNA level and total bilirubin level with Th17 frequency or plasm IL-17A levels were found. Furthermore, Treg/Th17 ratio was negatively correlated with total bilirubin levels (r = −0.41, p = 0.004) in chronic HBV-infected patients, especially in patients with ACHBLF (r = −0.69,p = 0.001) and positively correlated with viral load in these chronic HBV-infected subjects (r = 0.55, p<0.0001).

Conclusions

Th17 cells are involved in acute and chronic HBV infection, especially in AHB and ACHBLF. CHB and ACHBLF patients manifested obvious Treg/Th17 ratio imbalance, which might be linked to disease progression and the continuous HBV infection.

[stef2011]

Viral Immunol. 2013 Oct;26(5):336-42. doi: 10.1089/vim.2013.0032. Epub 2013 Sep 12.
Kinetics of Th17 cytokines during telbivudine therapy in patients with chronic hepatitis B.
Hao C1, Wang J, Kang W, Xie Y, Zhou Y, Ma L, Peng M, Bai X, Lian J, Jia Z.
Author information
Abstract
Th17 cells and the secreting cytokines play an important role in the immune response and inflammation that is induced by hepatitis B virus (HBV). However, it remains not fully elucidated how the antiviral agents affect Th17 cytokines and signal pathway. Telbivudine therapy has been proved to inhibit HBV replication effectively and to improve clinical outcome of chronic hepatitis B (CHB). Thus, in this study, the effect of decrease in viral load and liver dysfunction resulting from telbivudine treatment on Th17 cells and the related cytokines IL-17, IL-22, and IL-23 were analyzed. Peripheral blood mononuclear cells and serum from twenty-four CHB patients were harvested at 0, 12, 24, 36, and 48 weeks after initiation of telbivudine treatment. In parallel to the reduction of HBV DNA and normalization of serum ALT, significant declines in circulating HBV-specific Th17 cells and IL-22 production were found during antiviral therapy. The expression of serum IL-22 and IL-23, but not IL-17 also decreased during therapy. Our findings suggest that antiviral effect of telbivudine may attribute to both direct virus inhibition and regulation of inflammation, which further improve the understanding of pathogenesis of HBV infection and develop antiviral strategy for controlling viral hepatitis.

[stef2011]

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0096080

Abstract

Background and Aims

An immune imbalance in the cytokine profile exerts a profound influence on the progression of hepatitis B virus (HBV) infections and hepatocellular carcinoma (HCC). The present study evaluated the immune status of T helper (Th) 17 and Th1 cells in patients with HBV-related and non-HBV-related HCC.

Methods

We randomly enrolled 150 patients with HCC. Blood samples and tissue samples were obtained. The distributions and phenotypic features of Th17 and Th1 cells were determined by flow cytometry and/or immunohistochemistry.

Results

Compared to corresponding non-tumor regions, the levels of Th17 and Th1 cells were significantly increased in tumors of patients with HCC (P<0.001). The intratumoral densities of IL-17-producing cells and IFN-γ-producing cells were associated with overall survival (OS, P = 0.001) and disease-free survival (DFS, P = 0.001) of patients with HCC. The ratio of Th17 to Th1 in HBV-related HCC was higher than in non-HBV-related HCC. A multivariate Cox analysis revealed that the Th17 to Th1 ratio was an independent prognostic factor for OS (HR = 2.651, P = 0.007) and DFS (HR = 2.456, P = 0.002).

Conclusions

HBV infections can lead to an imbalance in immune status in patients with HCC. An elevated Th17 to Th1 ratio may promote tumor progression. The Th17 to Th1 ratio could serve as a potential prognostic marker for scoring the severity of HCC

[stef2011]

http://www.ncbi.nlm.nih.gov/pubmed/20492330

Circulating Th17 cells frequency is associated with the disease progression in HBV infected patients.
Wu W1, Li J, Chen F, Zhu H, Peng G, Chen Z.
Author information
Abstract
BACKGROUND AND AIMS:
Th17 cells have been shown to mediate host defensive mechanisms in various infections, but their role in HBV infection in humans has not been well characterized. In this study, we analyzed the frequency and cytokines secretion of circulating Th17 cells in HBV infected patients with different statuses, and also evaluated the potential association of Th17 frequency with the levels of liver injury.
METHODS:
The study population consisted of 133 subjects, including 40 mild chronic hepatitis B (CHB) patients, 37 severe CHB patients, 20 acute hepatitis B (AHB) patients and 36 healthy controls. The frequency of circulating Th17 cells were carried out by intracellular cytokine staining analysis and serum IL-10 levels were measured by ELISA.
RESULTS:
Our data shown that AHB and severe CHB patients had a significant increase of Th17 cells frequency in peripheral blood compared with mild CHB patients and healthy control (both P < 0.05). The elevated prevalence of Th17 cells is positively associated with the increased serum ALT levels in severe CHB patients (r= 0.457, P= 0.004) but had no correlation with serum HBV DNA load. In addition, the serum IL-10 were negatively correlated with the frequency of Th17 cells in PBMC from patients with chronic HBV infection (r=-0.452, P < 0.01).
CONCLUSION:
Th17 cells may contribute to the disease progression and pathogenesis of liver injury in HBV infected patients, and the induction of IL-10 may be one mechanism of constraining pro-inflammatory Th17 responses.

[stef2011]

the most interesting part

Treatment with antibodies to IL-17 inhibits viral persistence and disease development

Recent reports indicate that Th17 cells and their cytokine IL-17 play a pivotal role in tissue inflammation and damage, causing CNS demyelination in experimental autoimmune encephalomyelitis and perhaps also in human multiple sclerosis (4, 11). To determine whether this T cell type is also involved in the establishment of viral persistence and the consequent pathogenesis of chronic demyelinating disease, either neutralizing anti–IL-17 antibodies or isotype control antibodies were administered to LPS-treated B6 mice at days 0, 7, and 14 relative to TMEV infection (Fig. 4, A–F). Treatment with anti–IL-17 antibody reduced serum IL-17 to nearly undetectable levels during acute viral infection (8 d after infection) compared with treatment with isotype antibody, indicating the effectiveness of neutralizing antibodies (Fig. S3 A, available at http://www.jem.org/cgi/content/full/jem.20082030/DC1). Interestingly, IFN-γ and IL-17 levels produced by splenocytes in response to CD4 epitopes, UV-TMEV, and CD8 epitopes in the control group treated with isotype antibodies were comparable with mice treated with anti–IL-17 antibody (Fig. 4 A), suggesting that anti–IL-17 antibody treatment neutralizes IL-17 without eliminating Th17 cells. However, cellular infiltration (CD45hi leukocytes and CD45hiCD11b+ macrophages) to the CNS was decreased by more than twofold at day 8 after infection. Levels of Th17-associated IL-6, KC, and MCP-1 were also lower in the CNS of anti–IL-17 antibody–treated mice than in isotype antibody–treated mice (Fig. 4, B and C). Despite low levels of leukocyte infiltration in anti–IL-17 antibody–treated mice, IFN-γ and IL-17 production by CD4+ T cells (Fig. 4 D) and IFN-γ production by CD8+ T cells (Fig. S3 B) in the CNS were uncompromised. We further analyzed whether TMEV persists and induces chronic demyelinating disease in these antibody-treated mice. Viral persistence in the CNS was significantly lower at days 8 and 21 after infection in the anti–IL-17–treated group versus the control antibody–treated group (Fig. 4 E and Fig. S4 C). Furthermore, drastic reductions (P < 0.01) in the incidence and severity of demyelinating disease were observed in the anti–IL-17–treated group compared with control groups of LPS-treated B6 (Fig. 4 F) and susceptible SJL mice (Fig. 4 G). Histological examinations of these anti–IL-17 antibody–treated groups displayed very little cellular infiltration and demyelination in spinal cords, in contrast to extensive demyelination and cellular infiltration in isotype control groups (Fig. S4, A and B). Thus, the elimination of IL-17 function from virus-infected mice appears to prevent the development of demyelinating disease. These results clearly indicate that IL-17 plays a critical pathogenic role in the establishment of viral persistence and pathogenesis of chronic demyelinating disease in both temporarily converted genetically resistant B6 mice that have become susceptible after LPS treatment (Fig. 4 F) and genetically susceptible SJL mice (Fig. 4 G).