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

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ABSTRACT

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.

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(a) Degranulation activity of IH-NK cells of chronic HBV- and HCV-infected patients directly after the recovery of liver biopsies. Gaussian distribution was tested by the D'Agostino-Pearson omnibus normality test. The Mann-Whitney test was used to test the HBV cohort and the t-test to test the HCV cohort. (b) Frequencies of degranulating IH-NK CD56Dim cells of chronically HBV-infected patients stimulated in vitro by ±3 h of K562 target cells. The Mann-Whitney test was used to compare between females and males, while the Wilcoxon matched-pairs signed-rank test was used to compare before and after K562 stimulation. (c) Correlation of estradiol serum levels with spontaneous degranulation capacity of intrahepatic NK cells of chronically HBV-infected patients. To test significance, Pearson's correlation coefficients were used. Each symbol represented a patient and mean values are indicated by lines.
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fig1: (a) Degranulation activity of IH-NK cells of chronic HBV- and HCV-infected patients directly after the recovery of liver biopsies. Gaussian distribution was tested by the D'Agostino-Pearson omnibus normality test. The Mann-Whitney test was used to test the HBV cohort and the t-test to test the HCV cohort. (b) Frequencies of degranulating IH-NK CD56Dim cells of chronically HBV-infected patients stimulated in vitro by ±3 h of K562 target cells. The Mann-Whitney test was used to compare between females and males, while the Wilcoxon matched-pairs signed-rank test was used to compare before and after K562 stimulation. (c) Correlation of estradiol serum levels with spontaneous degranulation capacity of intrahepatic NK cells of chronically HBV-infected patients. To test significance, Pearson's correlation coefficients were used. Each symbol represented a patient and mean values are indicated by lines.

Mentions: Immune cells from blood and from fresh liver biopsies of infected patients (Supplementary Table 1) were analyzed by flow cytometry. Among CD45high+ population, NK cells were identified (Supplementary Figure 1A). To investigate the NK cell cytolytic properties, we determined the CD107a expression, which is considered a marker of degranulation, that is, release of lytic granules toward the target cells [12, 13]. Mean percentage of CD107a+ IH-NK cells was significantly higher in liver biopsies from HBV-infected females (n = 16) compared to HBV-infected males (n = 27), with a frequency of CD107a+ IH-NK 8.4 ± 1.2% in females compared to 4.5 ± 0.6% in males (Figure 1(a)). In HCV-infected patients, the frequency of CD107+ IH-NK cells was similar between females (4.7 ± 0.6%, n = 39) and males (5.1 ± 0.4%, n = 43).


Sex Differences in Spontaneous Degranulation Activity of Intrahepatic Natural Killer Cells during Chronic Hepatitis B: Association with Estradiol Levels
(a) Degranulation activity of IH-NK cells of chronic HBV- and HCV-infected patients directly after the recovery of liver biopsies. Gaussian distribution was tested by the D'Agostino-Pearson omnibus normality test. The Mann-Whitney test was used to test the HBV cohort and the t-test to test the HCV cohort. (b) Frequencies of degranulating IH-NK CD56Dim cells of chronically HBV-infected patients stimulated in vitro by ±3 h of K562 target cells. The Mann-Whitney test was used to compare between females and males, while the Wilcoxon matched-pairs signed-rank test was used to compare before and after K562 stimulation. (c) Correlation of estradiol serum levels with spontaneous degranulation capacity of intrahepatic NK cells of chronically HBV-infected patients. To test significance, Pearson's correlation coefficients were used. Each symbol represented a patient and mean values are indicated by lines.
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getmorefigures.php?uid=PMC5392396&req=5

fig1: (a) Degranulation activity of IH-NK cells of chronic HBV- and HCV-infected patients directly after the recovery of liver biopsies. Gaussian distribution was tested by the D'Agostino-Pearson omnibus normality test. The Mann-Whitney test was used to test the HBV cohort and the t-test to test the HCV cohort. (b) Frequencies of degranulating IH-NK CD56Dim cells of chronically HBV-infected patients stimulated in vitro by ±3 h of K562 target cells. The Mann-Whitney test was used to compare between females and males, while the Wilcoxon matched-pairs signed-rank test was used to compare before and after K562 stimulation. (c) Correlation of estradiol serum levels with spontaneous degranulation capacity of intrahepatic NK cells of chronically HBV-infected patients. To test significance, Pearson's correlation coefficients were used. Each symbol represented a patient and mean values are indicated by lines.
Mentions: Immune cells from blood and from fresh liver biopsies of infected patients (Supplementary Table 1) were analyzed by flow cytometry. Among CD45high+ population, NK cells were identified (Supplementary Figure 1A). To investigate the NK cell cytolytic properties, we determined the CD107a expression, which is considered a marker of degranulation, that is, release of lytic granules toward the target cells [12, 13]. Mean percentage of CD107a+ IH-NK cells was significantly higher in liver biopsies from HBV-infected females (n = 16) compared to HBV-infected males (n = 27), with a frequency of CD107a+ IH-NK 8.4 ± 1.2% in females compared to 4.5 ± 0.6% in males (Figure 1(a)). In HCV-infected patients, the frequency of CD107+ IH-NK cells was similar between females (4.7 ± 0.6%, n = 39) and males (5.1 ± 0.4%, n = 43).

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus