Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population

Abstract

SummaryPrimary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by progressive loss of intrahepatic small bile ducts. Cellular immune mechanisms involving T cell reaction are thought to be involved significantly in the pathogenesis of PBC. Recent studies have independently revealed enhanced T helper type 17 (Th17) response and weakened T regulatory cell (Treg) response in some autoimmune diseases, indicating a role of Th17/Treg imbalance in the pathogenesis of autoimmunity. This prompted us to investigate whether the Th17/Treg balance was broken in the peripheral blood of patients with PBC and, if it was, what cytokine circumstances might contribute to this imbalance. The expression of 11 Th17/Treg differentiation-related genes and serum concentrations of the corresponding cytokines in 36 patients with PBC, 28 patients with chronic hepatitis B and 28 healthy controls were measured by real-time quantitativepolymerase chain reaction and enzyme-linked immunosorbent assay respectively. Peripheral Th17 and Treg cells were analysed by flow cytometry. Th17-related cytokines were increased significantly in patients with PBC. Consistent with the cytokine profile, the Th17 cell population and retinoidrelated orphan receptor gt expression were increased markedly. In contrast, the Treg cell population and forkhead box P3 expression were decreased dramatically in the peripheral blood of patients with PBC. Our study revealed that the Th17/Treg imbalance, both cytokine profile and cell numbers, exists in patients with PBC, suggesting its potential role in the breakdown of immune self-tolerance in PBC. Interleukin-23, which characterized the imbalanced cytokine profile, may play an essential role in Th17-related human autoimmunity.

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

“…The plasma TGF-β concentration in patients with early-stage PBC was lower than the concentration in healthy individuals, consistent with the Th17-Treg imbalance in PBC. However, the concentration was higher in patients with late-stage PBC than in healthy individuals, a result that seems to be different from those of Rong et al (2009). Previous studies showed that TGF-β and IL-6 expression levels are elevated in the fibrotic process in PBC, whereas the inflammatory process involves decreased TGF-β and increased Th17 expression levels (Fenoglio et al 2012).…”

“…Patients with PBC showed below-normal numbers of circulating CD4+CD25 high Tregs (Wang et al 2010;Wang et al 2015b), and UDCA treatment for 1 year increased these numbers (Lacerda et al 1995). Rong et al (2009) reported increased IL-23 and IL-6 and decreased TGF-β concentrations in the circulation of patients with PBC. Taken together, these findings highlight the activation of Th17 and inhibition of Tregs in PBC (Rong et al 2009).…”

“…Rong et al (2009) reported increased IL-23 and IL-6 and decreased TGF-β concentrations in the circulation of patients with PBC. Taken together, these findings highlight the activation of Th17 and inhibition of Tregs in PBC (Rong et al 2009). This explanation is supported by evidence that PBC patients show decreased numbers of Foxp3+ Tregs in peripheral blood, and that IL-17+ cells accumulated around damaged bile ducts (Fenoglio et al 2012).…”

“…Tregs, which secrete TGF-β, play an important role in preventing autoimmune reactions (Filaci et al 2011;Yamaguchi et al 2011;Sakaguchi et al 2012). PBC is characterized by a Treg-Th17 cell imbalance, as evidenced by the increased IL-23 and IL-6 but decreased TGF-β expression levels in plasma from patients with PBC (Rong et al 2009). Th1 cells are important in this disease and can form an IL-12 expression feedback loop through IFN-γ (Webb et al 2015).…”

Role of Interleukin-17 in the Development of Hepatocellular Carcinoma in Hepatitis C Virus Liver Cirrhosis

“…CD4 T-cell responses play a critical role in the resolution of infection and impaired HCV-specific CD4 Tcell responses are observed in chronic HCV [6] . Interleukin (IL)-17-producing T-helper (Th)17 cells have been reported to trigger tissue inflammation and damage [7] and there is accumulating evidence that Th17 cells are important contributors to hepatic inflammation and liver cirrhosis [8] . Th17 cells and its signature cytokine, interleukin-17 (IL-17), have been found increased frequencies within certain tumors .…”