Sex Differences in Spontaneous Degranulation Activity of Intrahepatic Natural Killer Cells during Chronic Hepatitis B: Association with Estradiol Levels.

Major sex differences are observed in the prevalence, intensity, and severity of hepatitis B virus (HBV) infection. Here, we investigated degranulation activity of circulating and intrahepatic natural killer (NK) cells from HBV and HCV chronically infected patients before any treatment (n = 125). The frequency of CD107+ NK cells in the female liver was significantly higher compared to that in males during chronic HBV infection (p = 0.002) and correlated with the plasma levels of estradiol (correlation coefficient r = 0.634; p < 0.0001). Our results clearly show sex differences in degranulation activity of intrahepatic NK cells of HBV-infected patients. This probably contributes to the ability of females to better deal with HBV disease.

Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17(+) neutrophils.

BACKGROUND & AIMS: The pro-inflammatory cytokine IL-17 plays a crucial role in liver diseases associated with hepatic fibrosis and increased risk of cancer development. Nevertheless, the cellular source of this cytokine has never been characterized in patients with liver fibrosis. METHODS: In this study, we investigated liver biopsies from 49 patients with chronic viral hepatitis at different stages of liver fibrosis. We monitored IL-17 production by intracellular flow cytometry, immunofluorescence and immunohistochemical in situ stainings, allowing a precise quantification, characterization and localization of IL-17(+) cells. RESULTS: Density of IL-17(+) cells increased with the stage of liver fibrosis specifically in fibrotic septa and portal areas (correlation coefficient r = 0.7373; P < 0.0001). Data clearly show that the frequency of intrahepatic IL-17(+) lymphocytes (including T, NKT and NK cells) was independent on stage of liver fibrosis, and we observed no statistical differences in number of IL-17(+) macrophages during progression of fibrosis. On the other hand, the number of IL-17(+) neutrophils in fibrotic septa and portal areas strongly correlated with the stages of fibrosis (correlation coefficient r = 0.6986; P < 0.0001), contributing significantly to total IL-17 production in liver tissue. CONCLUSIONS: Our data indicate that neutrophils represent an important source of IL-17 in the human liver, especially in late fibrosis stages. Inhibition of this specific harmful subset of neutrophils may offer therapeutic opportunities in fibrotic liver.

Functions of liver natural killer cells are dependent on the severity of liver inflammation and fibrosis in chronic hepatitis C.

During chronic hepatitis C virus (HCV) infection, the role of intra-hepatic (IH) natural killer (NK) cells is still controversial. To clarify their functions, we investigated anti-viral and cytotoxic activity of NK cells in human fresh liver biopsies. We compared the functions of IH-NK cells in HCV-infected and NASH patients in physiological conditions as well as after stimulation using flow cytometric and immunohistochemical analyses. Interestingly, few IH-NK cells produced anti-viral cytokine IFN-γ in HCV-infected patients similarly as in non-infected individuals. Spontaneous degranulation activity was extremely low in peripheral NK cells compared to IH-NK cells, and was significantly higher in IH-NK cells from HCV-infected patients compared to non-infected individuals. Immunohistochemical analysis revealed that perforin granules were polarized at the apical pole of IH-NK cells. The presence of CD107a and perforin in IH-NK cells demonstrated that NK cells exerted a cytolytic activity at the site of infection. Importantly, IH-NK cell functions from HCV-infected patients were inducible by specific exogenous stimulations. Upon ex vivo K562 target cell stimulations, the number of degranulating NK cells was significantly increased in the pool of IH-NK cells compared to circulating NK cells. Interestingly, after stimulation, the frequency of IFN-γ-producing IH-NK cells in HCV-infected patients was significantly higher at early stage of inflammation whereas the spontaneous IH-NK cell degranulation activity was significantly impaired in patients with highest inflammation and fibrosis Metavir scores. Our study highlights that some IH-NK cells in HCV-infected patients are able to produce INF-γ and degranulate and that those two activities depend on liver environment including the severity of liver injury. Thus, we conclude that critical roles of IH-NK cells have to be taken into account in the course of the liver pathogenesis associated to chronic HCV infection.

Lymphocytes degranulation in liver in hepatitis C virus carriers is associated with IFNL4 polymorphisms and ALT levels.

BACKGROUND: The polymorphisms of IFNL4 are strongly associated with both spontaneous hepatitis C virus (HCV) clearance and response to peg-IFN-α/ribavirin treatment. To further establish the biological effects of the IFNL4 and rs1297860 variations, we studied the activity of liver immune cells. METHODS: Fresh liver samples were collected from HCV-infected patients before any treatment and from NASH patients as controls. Degranulation activity of each lymphocyte type was assessed by the surface expression of CD107a. IFNL4 polymorphisms and HCV genotypes were determined. RESULTS: In the liver, frequency of CD107a(+) immune cells was significantly higher in HCV patients compared to NASH patients. Higher degranulation activity was observed in lymphocytes of HCV patients with favorable IFNL4 genotypes compared to patients with unfavorable genotypes. Multivariate regression analyses indicated that serum ALT levels were dependent on both Metavir activity score and frequency of CD107a positive NKT cells. The high level of degranulation activity observed before treatment was associated with a high HCV RNA decline at the early stage of peg-IFN-α/ribavirin treatment in patients with favorable genotypes. CONCLUSIONS: These data underline that intrahepatic lymphocyte degranulation activity in HCV-infected patients is associated with IFNL4 polymorphisms and contributes to the clearance of HCV in patients with favorable genotypes under antiviral therapy.

Participation behavior of bladder cancer survivors in a medical follow-up survey on quality of life in France.

The objectives were to ascertain the sociodemographic background of bladder cancer survivors acting on their participation behavior to a medical follow-up survey. This population-based quality of life (QOL) survey was realized by mail with 201 survivors (M:F = 171:30, median age = 74 years, range 33-99) randomly selected from the 1731 patients diagnosed between 1990 and 1994 in two regions of France. Response rate was 47.3%. Female and younger survivors were more receptive to the survey than were males and older survivors. Furthermore, survivors who had experienced a cystectomy were more responsive than those who did not. Similarly, the length of time since a major treatment was significant, with a shorter interval associated with a better response. The missing item rate in the QOL questionnaire was 13.8%. Other variables were not significantly associated with acceptance of the survey. Missing items among the responders were found more often in the sub-scale of social/familial well-being (15.6%). The older and male subjects left more questions blank. The reason for this low response rate can be categorized to the following three points: (1) Physically and psychologically not motivated to answer, (2) sensitive and private content of the question, and (3) methodological problem. Clearer concepts of the research would have helped the participants understand the objectives and better relate to the survey. Subsequently, these three issues should be given more attention in organizing questionnaire survey for improved participation rates in future studies.