Significance of the Balance between Regulatory T (Treg) and T Helper 17 (Th17) Cells during Hepatitis B Virus Related Liver Fibrosis

Abstract

BackgroundHepatitis B virus-related liver fibrosis (HBV-LF) always progresses from inflammation to fibrosis. However, the relationship between these two pathological conditions is not fully understood. Here, it is postulated that the balance between regulatory T (Treg) cells and T helper 17 (Th17) cells as an indicator of inflammation may predict fibrosis progression of HBV-LF.Methodology/Principal FindingsThe frequencies and phenotypes of peripheral Treg and Th17 cells of seventy-seven HBeAg-positive chronic hepatitis B (CHB) patients who underwent liver biopsies and thirty healthy controls were determined by flow cytometry. In the periphery of CHB patients, both Treg and Th17 frequencies were significantly increased and correlated, and a lower Treg/Th17 ratio always indicated more liver injury and fibrosis progression. To investigate exact effects of Treg and Th17 cells during HBV-LF, a series of in vitro experiments were performed using purified CD4+, CD4+CD25+, or CD4+CD25− cells from the periphery, primary human hepatic stellate cells (HSCs) isolated from healthy liver specimens, human recombinant interleukin (IL)-17 cytokine, anti-IL-17 antibody and HBcAg. In response to HBcAg, CD4+CD25+ cells significantly inhibited cell proliferation and cytokine production (especially IL-17 and IL-22) by CD4+CD25− cells in cell-contact and dose-dependent manners. In addition, CD4+ cells from CHB patients, compared to those from HC subjects, dramatically promoted proliferation and activation of human HSCs. Moreover, in a dramatically dose-dependent manner, CD4+CD25+ cells from CHB patients inhibited, whereas recombinant IL-17 response promoted the proliferation and activation of HSCs. Finally, in vivo evidence about effects of Treg/Th17 balance during liver fibrosis was obtained in concanavalin A-induced mouse fibrosis models via depletion of CD25+ or IL-17+ cells, and it’s observed that CD25 depletion promoted, whereas IL-17 depletion, alleviated liver injury and fibrosis progression.Conclusions/SignificanceThe Treg/Th17 balance might influence fibrosis progression in HBV-LF via increase of liver injury and promotion of HSCs activation.

Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8+T cell

“…6). In addition, several studies have reported that decreased frequency of Treg also results in significantly higher Th17 cells in HBV-infected patients, [58][59][60] which is consistant with our results (Fig. 3D).…”

MiR-29a and miR-652 Attenuate Liver Fibrosis by Inhibiting the Differentiation of CD4+ T Cells

“…is a pro-inflammatory cell that plays vital role on host defenses and several autoimmune disorders through releasing of cytokines such as , and both IL-17A and IL-22 functioned to control of extracellular bacterial infection (Shigematsu et al, 2013). Studies have demonstrated that the level of Th17 cells were significantly increased in patients with liver diseases, additionally, the increasingly level of Th17 cells also promoted the progression of liver fibrosis (Li et al, 2012b). While the levels of IL-17A and IL-22 in the liver tissues were always considered as the main factors to measure liver function.…”

Immunomodulatory effect of bone marrow mesenchymal stem cells on T lymphocytes in patients with decompensated liver cirrhosis

“…Our research found that, when compared with healthy people, patients with decompensated cirrhosis have a lower incidence of peripheral Tregs, a higher incidence of Th17, and a Treg/Th17 imbalance. As a result, some researchers consider that Treg and Th17 cells inhibit and promote inflammatory reactions, respectively, and disruptions in the balance between the two contribute greatly to the progression of chronic hepatitis B to cirrhosis and liver failure (Li et al, 2012b). Some researchers have indicated that MSCs can change the composition of T cell subsets, secrete transforming growth factor TGF-β1 and prostaglandin E2, induce the proliferation of Treg cells (De Miguel et al, 2012;Soleymaninejadian et al, 2012), and inhibit the expression of Th17 cells through the CCL2 pathway (Rafei et al, 2009).…”