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.
Highlights
Worldwide, hepatitis B virus (HBV) affects over 350 million individuals and continues to cause more than a million deaths annually from end-stage liver diseases [1]. HBV itself is noncytopathic, it causes chronic immune-induced liver injury and forces disease progression from mild inflammation, to severe inflammation, to fibrosis, and to cirrhosis
We found the CD4+CD25+ cells from chronic hepatitis B (CHB) patients could significantly down-regulate the concentrations of IL-17 and IL-22 in the co-culture systems, which were probably produced by T helper 17 (Th17) cells existing in CD4+CD252 cells, and this effect was only observed when the co-cultures were performed in contact manner (Figure 4C)
Both Treg and Th17 responses have been described in CHB patients [4,5,6,9,10,14], the significance of the Treg/Th17 balance during fibrosis progression of Hepatitis B virus-related liver fibrosis (HBV-LF) has not been determined
Summary
Hepatitis B virus (HBV) affects over 350 million individuals and continues to cause more than a million deaths annually from end-stage liver diseases [1]. HBV itself is noncytopathic, it causes chronic immune-induced liver injury and forces disease progression from mild inflammation, to severe inflammation, to fibrosis, and to cirrhosis. The most recent concerns regulatory T (Treg) cells, a subset of CD4+ cells suppressing immune responses to maintain unresponsiveness to self-antigens and prevent excessive immune responses to foreign antigens, which play an important role in autoimmune and infectious diseases [2]. These cells can be generated in the thymus as naturally-occurred Treg or in the periphery as induced Treg. CD4+CD25+Foxp3+ cells have recently been reported to increase in chronic hepatitis B (CHB) patients, which could inhibit HBV-specific CD8+ T cell response and show a close association with HBV loads and serum alanine aminotransferase (ALT) levels [4,5,6]. 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
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