[Show abstract][Hide abstract] ABSTRACT: The role of IL28B gene variants and expression in hepatitis B virus (HBV) infections are not well understood. Here, we evaluated whether IL28B gene expression and rs12979860 variations are associated with HBV outcomes.
IL28B genetic variations (rs12979860) were genotyped by pyrosequencing of DNA samples from 137 individuals with chronic HBV infection [50 inactive carriers (IC), 34 chronic hepatitis B (CHB), 27 cirrhosis, 26 hepatocellular carcinoma (HCC)], and 19 healthy controls. IL28A/B mRNA expression in peripheral blood mononuclear cells was determined by qRT-PCR, and serum IL28B protein was measured by ELISA.
Patients with IL28B C/C genotype had greater IL28A/B mRNA expression and higher IL28B protein levels than C/T patients. Within the various disease stages, compared to IC and healthy controls, IL28B expression was reduced in the CHB, cirrhosis, and HCC cohorts (CHB vs. IC, p=0.02; cirrhosis vs. IC, p=0.01; HCC vs. IC, p=0.001; CHB vs. controls, p<0.01; cirrhosis vs. controls, p<0.01; HCC vs. controls, p<0.01). When stratified with respect to serum HBV markers in the IC and CHB cohorts, IL28B mRNA and protein levels were higher in HBeAg-positive than negative individuals (p=0.01). Logistic regression analysis revealed that factors associated with high IL28B protein levels were C/C versus C/T genotype [p=0.016, odds ratio (OR)=0.25, 95% confidence interval (CI)=0.08-0.78], high alanine aminotransferase values (p<0.001, OR=8.02, 95% CI=2.64-24.4), and the IC stage of HBV infection (p<0.001).
Our data suggest that IL28B genetic variations may play an important role in long-term development of disease in chronic HBV infections.
Yonsei medical journal 05/2015; 56(3):625-33. DOI:10.3349/ymj.2015.56.3.625 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TRIM22, a tripartite-motif (TRIM) protein, is upregulated upon interferon alpha (IFNα) administration to hepatitis C virus (HCV)-infected patients. However, the physiological role of TRIM22 upregulation remains unclear. Here, we describe a potential antiviral function of TRIM22's targeting of the HCV NS5A protein. NS5A is important for HCV replication and for resistance to IFNα therapy. During the first 24 h following the initiation of IFNα treatment, upregulation of TRIM22 in the peripheral blood mononuclear cells (PBMCs) of HCV patients correlated with a decrease in viral titer. This phenomenon was confirmed in the hepatocyte-derived cell line Huh-7, which is highly permissive for HCV infection. TRIM22 over-expression inhibited HCV replication, and Small interfering RNA (siRNA)-mediated knockdown of TRIM22 diminished IFNα-induced anti-HCV function. Furthermore, we determined that TRIM22 ubiquitinates NS5A in a concentration-dependent manner. In summary, our results suggest that TRIM22 upregulation is associated with HCV decline during IFNα treatment and plays an important role in controlling HCV replication in vitro.Cellular & Molecular Immunology advance online publication, 16 February 2015; doi:10.1038/cmi.2014.131.
[Show abstract][Hide abstract] ABSTRACT: The interleukin-28B gene (IL28B) locus has been associated with host resistance to hepatitis C virus (HCV) infection and response to PEG-IFN/RBV treatment in western populations. This study was to determine whether this gene variant is also associated with spontaneous clearance of HCV infection, treatment response and IL-28B protein production in Chinese patients.
We genotyped IL28B genetic variations (rs12980275, rs8103142, rs8099917 and rs12979860) by pyrosequencing DNA samples from cohorts consisting of 529 subjects with persistent HCV infection, 196 subjects who cleared the infection, 171 healthy individuals and 235 chronic HCV patients underwent IFN/RBV treatment. The expression of IL-28B were measured by ELISA and RT-PCR.
We found that the four IL28B variants were in complete linkage disequilibrium (r2 = 0.97-0.98). The rs12979860 CC genotype was strongly associated with spontaneously HCV clearance and successful IFN/RBV treatment compared to the CT/TT. IL-28B levels in persistent HCV patients were significantly lower than subjects who spontaneously resolved HCV and healthy controls and were also associated with high levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase). IL-28B levels were also significantly lower in individuals carrying T alleles than CC homozygous.
Thus, the rs12979860-CC variant upstream of IL28B gene is associated with spontaneous clearance of HCV, susceptible to IFN/RBV treatment and increased IL-28B levels in this Chinese population.
PLoS ONE 05/2012; 7(5):e37054. DOI:10.1371/journal.pone.0037054 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
T follicular helper (TFH) cells are a special subpopulation of T helper cells and can regulate humoral immune responses. This study examined whether the frequency of CD4+CXCR5+ TFH cells could be associated with active immunity in chronic hepatitis B (CHB) patients.
Methodology and Findings
The frequencies of peripheral blood CD4+CXCR5+ TFH cells, inducible T cell costimulator (ICOS), and/or programmed death 1 (PD-1) positive CD4+CXCR5+ TFH cells in immune-active (IA), immune-tolerant (IT) CHB, and healthy controls (HC) were characterized by flow cytometry analysis. The effect of adevofir dipivoxil treatment on the frequency of CD4+CXCR5+ TFH cells, the concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-21, ALT, AST, HBsAg, HBsAb, HBeAg, HBeAb and HBV loads in IA patients were determined. The potential association of the frequency of CD4+CXCR5+ TFH cells with clinical measures was analyzed. In addition, the frequency of splenic and liver CD4+CXCR5+ TFH cells in HBV-transgenic mice was examined. We found that the frequency of CD4+CXCR5+ TFH cells in IA patients was significantly higher than that of IT patients and HC, and the percentages of CD4+CXCR5+ TFH in IA patients were positively correlated with AST. Furthermore, the percentages of ICOS+, PD-1+, and ICOS+PD-1+ in CD4+CXCR5+ TFH cells in CHB patients were significantly higher than that of HC. Treatment with adefovir dipivoxil reduced the frequency of CD4+CXCR5+ TFH, PD-1+CD4+CXCR5+ TFH cells and the concentrations of HBsAg and HBeAg, but increased the concentrations of HBsAb, HBeAb, IL-2 and IFN-γ in IA patients. Moreover, the frequency of splenic and liver CD4+CXCR5+ TFH cells in HBV-transgenic mice was higher than that of wild-type controls.
These data indicate that CD4+CXCR5+ TFH cells may participate in the HBV-related immune responses and that high frequency of CD4+CXCR5+ TFH cells may be a biomarker for the evaluation of active immune stage of CHB patients.
PLoS ONE 07/2011; 6(7):e21698. DOI:10.1371/journal.pone.0021698 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prevalence of the hepatitis B virus (HBV) is higher in adults than in children. We determined the seroepidemiology of HBV infection in an adult population in JiLin, China, to guide effective preventive measures.
A cross-sectional serosurvey was conducted throughout JiLin, China. A total of 3833 people was selected and demographic and behavioral information gathered. Serum samples were tested for HBV markers and liver enzymes.
The prevalence of the hepatitis B surface antigen (HBsAg), the antibody to the hepatitis B surface antigen (anti-HBs), the hepatitis B e antigen (HBeAg), the antibody to HBeAg (anti-HBe), and the antibody to the hepatitis B core antigen (anti-HBc) were 4.38%, 35.66%, 1.38%, 6.65%, and 40.88%, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly higher among HBsAg (+) than HBsAg (-) subjects. By multivariate logistic regression analysis, independent predictors for chronic HBV infection were smoking, poor sleep quality; occupation as private small-businessmen, laborers, or peasants; male gender; family history of HBV; personal history of vaccination; and older age. Independent predictors for exposure to HBV were large family size, occupation as a private small-businessman, male gender, family history of HBV, personal history of vaccination, and older age. Independent predictors for immunity by vaccination were occupation as a private small-businessman, high income, personal history of vaccination, and young age. Independent predictors for immunity by exposure were drinking, male gender, personal history of vaccination, and older age.
The prevalence rate of HBV infection (4.38%) was lower than the previous rate of general HBV vaccination. However, 44.59% of the population remained susceptible to HBV. The prevalence of HBV infection was high in young adults, private small-businessmen, peasants, those with a family history of HBV, and males. Therefore, immunization of the non-immune population is reasonable to reduce hepatitis B transmission between adults.
International journal of medical sciences 05/2011; 8(4):321-31. DOI:10.7150/ijms.8.321 · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent genome-wide association studies found that genetic polymorphisms near the IL28B gene is strongly associated with sustained viral response and spontaneous viral clearance in chronically infected hepatitis C patients.
We aimed to evaluate the effects of IL28B variations on hepatitis B virus (HBV) infection in a Chinese Han population and to explore the association between IL28B polymorphisms and susceptibility to infection, viral clearance, disease progression, viral load and liver inflammation. Methods: We determined three IL28B single gene polymorphisms (rs12979860, rs12980275 and rs8099917) in 203 individuals with chronic HBV infection, 203 individuals with self-limited HBV infection and 203 individuals negative for all HBV seromarkers. Interleukin (IL)28B serum levels were evaluated in all subjects. Additionally, peripheral blood mononuclear cells from 42 chronically HBV-infected individuals were subjected to whole-genome expression studies.
The association among genotype, allele and haplotype frequencies of IL28B with alanine aminotransferase levels and HBV DNA was established. However, no significant differences were observed in genotype or allele frequencies among chronically HBV-infected, self-limited and healthy subjects. The serum IL28B level was lower in patients with chronic HBV infection than in the self-limited HBV-infected or healthy subjects. The serum IL28B level was correlated with the subject's genotype. Gene expression micro-array analysis showed enhanced IL28B expression in patients with low HBV viral load.
Variability at the IL28B locus is associated with HBV viral load and hepatic inflammation. Genetic variation of IL28B may prevent HBV progression by reducing viral load and liver inflammation, providing a valuable gene therapy tool.
Liver international: official journal of the International Association for the Study of the Liver 03/2011; 31(8):1118-26. DOI:10.1111/j.1478-3231.2011.02507.x · 4.85 Impact Factor