Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes.
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Abstract:
In vitro studies in patients with hepatitis B virus (HBV) infection have suggested that hepatocytolysis induced by CD8+ cytotoxic T lymphocytes (CTLs) is the most important effector pathway in eliminating infected cells. The recognition is implicated in the endogenously processed HBV antigens in the context of HLA class I molecules presented on the liver cell membrane. However, the naturally occurring HBV peptide antigens have not yet been demonstrated. We report here that a naturally processed peptide antigen P2 was isolated from HLA class I molecules of HBV-infected liver cell membrane. The P2 peptide exhibited the activity of sensitizing target cells for lysis by CD8+ CTLs. The P2 sequence (YVNVNMGLK) purified from liver tissue was in concordance with that encoded by the viral genome for the HBV nucleocapsid antigen or HBcAg 88-96. P2 peptide could also be isolated from the EBV-transformed B cells that were transfected by HBcAg-expressing vector. The P2 epitope, sharing the HLA-A11 binding motifs, was recognized by HLA-A11-restricted CD8+ CTLs. The data provided direct evidence that, in hepatitis B patients, antigenic peptides of HBV were processed by hepatocytes, presented with the class I MHC molecules, and recognized by CD8+ CTLs.Keywords:
HBcAg
Expression and distribution of intrahepatic HBsAg and HBcAG were studied by double staining immunohistochemical assay in chronic liver disease. HBsAg was homogenously cytoplasmic in typing in 41 and HBcAg was cytoplasmic-membranous in 31 of 46 cases which were known to be positive for both HBsAg and HBcAg intrahepatically. The expressing sites of both HBsAg and HBcAg in 40 of the 46 cases were found to be positive in the same areas of the sections. Interestingly, it was found that intrahepatic HBsAg and HBcAg were often coexistent in the same hepatocyte, and these hepatocytes were considered to be further classifiable into type I and type II according to their distribution. The detective rate of type II cell was significantly higher during the HBV replication stage serologically. HBsAg and HBcAg coexpression in cytoplasm of hepatocyte was noticed to be closely related to active pathological change of the liver cells.
HBcAg
Liver disease
Chronic liver disease
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Objective: To investigate the expressions of HER-2/neu,HBsAg and HBcAg by SP reagents in 45 patients with hepatocellular carcinoma(HCC). Methods: All samples from HCC were immunohistochemically examined by SP reagents. Results: The expressions of HER-2/neu gene and HBsAg in HCC were significantly lower than those para-cancerous tissues (χ2 = 22.77,χ2 = 15.65,P 0.01). There was no significant difference for expression of HBcAg in HCC and para-cancerous tissues(χ2 = 2.70,P 0.05). HER-2/neu gene was positively related with HBsAg and HBcAg (χ2=17.78,r=0.532 and χ2=8.46,r=0.398). In the positive group of HER-2/neu, the expressions of HBsAg and HBcAg were significant higher than those of the negative group(χ2=12.69, P 0.01and χ2=5.08,P 0.05). Howerer para-cancerous tissues was positively related with HBsAg (χ2 = 15.33,r = 0.254) and was not related with HBcAg (χ2 = 0.126 7,P 0.05). In the positive group of HER-2/neu, the expressions of HBsAg in para-cancerous tissues were higher than those of the negative group (χ2=11.84,P 0.05). There were no significant differences in the expressions of HER-2/neu between Ⅰ+Ⅱgroup and Ⅲ+Ⅳgroup for the clinical classification (χ2=0.95,P 0.05). Conclusion: When the expression of HER-2 /neu gene was observed, the positive rate of HBsAg and HBcAg was both increased. With the stage of HCC in clinical stage, the expression of HER-2/neu gene inclined to decrease in para-cancerous tissues.
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The results of histological and immunohistological studies on the liver biopsies from patients with positive serum HBsAg, HBeAg, HBVDNA, and HBVDNAp showed: 1. In addition to the inclusion body like, marginal, diffuse and membranous patterns of HBsAg, we found that marginal and diffuse patterns of HBsAg may appear within one hepatocyte and this is named as transitional pattern. A preliminary suggestion about the process of formation and evolution of different patterns of HBsAg and HBcAg was raised. 2. There is a relationship between HBV replication and the activity of hepatitis. Different patterns and distributions of HBAg affect the lesion of the liver significantly. 3. According to the morphology of HBsAg and HBcAg, we suggest to divide their patterns into the following two categories: The first includes the diffuse and membranous patterns of HBsAg and the cytoplasmic and membranous HBcAg; these are related to the replication of HBVDNA. The second includes inclusion body like and marginal patterns of HBsAg with and without nuclear pattern of HBcAg; these probably reflect the integration of HBVDNA to the host genome.
HBcAg
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Background: Hepatitis B virus (HBV) infection is considered a major global health problem. The main objectives of the current study is to determine the patterns of expression of the hepatitis B surface antigen (HBsAg) and HBV core antigen (HBcAg) in liver tissue samples obtained from hepatitis B virus-infected Omani patients and to associate between the pattern of the expression of HBsAg and HBcAg with the other clinical parameters and anti-viral therapy. Methods : The expression patterns of HBsAg and HBV core antigen HBcAg were determined by immunohistochemistry (IHC), in 58 formalin-fixed paraffin-embedded liver tissue biopsies obtained from chronic hepatitis B Omani patients. The association between positivity for HBV antigens with gender, age group, histological appearances, and antiviral therapy was determined. Results: IHC-positive staining of HBsAg was demonstrated in 28 patients (48.3%) patients, of whom 4 (6.9%) also showed HBcAg expression. The expression pattern of HBsAg was predominantly cytoplasmic and was seen in 25 (89.3%) of patients, whereas expression of HBcAg was nuclear in 3 (75%) of patients. HBsAg and HBcAg IHC positivity were more common among males than females and among those aged 39–58 years (P = 0.130 and 0.569, respectively). The presence of lymphocytic infiltration in the majority of liver biopsies examined in the present study indicates that the liver damage could be attributed to immunologically mediated events, especially because HBV is a non-cytopathogenic virus. No significant statistical association was found between positivity for HBsAg/HBcAg by IHC and antiviral treatment. Conclusions: Determination of the expression patterns of HBV antigens in liver biopsies obtained from chronic hepatitis B Omani patients and the association between these expression patterns with other clinical histopathological parameters and anti-viral therapy, will contribute greatly to a better understanding of the pathogenesis of HBV in this unique cohort group of infected individuals.
HBcAg
Hepatitis B
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The correlation between serum and hepatic markers of hepatitis B virus (HBV) has been studied in 70 subjects with chronic active hepatitis of whom 18 were HBsAg+ and 52 were HBsAg-. In HBsAg+ subjects, sera were tested for HBeAg/anti-HBe status and for HBV DNA sequences using a DNA dot hybridization technique. Anti-HBs and anti-HBc were measured in serum in the HBsAg- group. Immunoperoxidase staining was used to detect HBsAg, HBcAg and delta antigen in liver tissue. Of the 18 HBsAg+ patients, 13 were HBeAg+ and 5 were anti-HBe+. A good correlation was shown between HBeAg and HBV DNA in serum and HBcAg expression in liver tissue. Neither HBV DNA in serum nor HBcAg in liver tissue was detected in any of the anti-HBe+ patients. HBsAg and/or HBcAg were detected in liver tissue in 17 of 18 HBsAg+ subjects (95%). However, neither HBsAg nor HBcAg were detected in liver tissue in 52 HBsAg- patients. This group included 11 patients with antibody markers in serum of past HBV infection. Thus, in contrast to previous studies, a good correlation was demonstrated between the serum and hepatic markers of viral replication, and no evidence was obtained to implicate the HBV as an etiological agent in HBsAg- chronic active hepatitis.
HBcAg
HBeAg
Hepatitis B
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The distribution of hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) in surgically removed liver cell carcinomas of 60 Japanese patients was studied by an immunohistochemical method. HBsAg was localized in the cytoplasm, and HBcAg was mainly in the nuclei of normal-appearing liver cells, dysplastic liver cells, and tumor cells. In some instances both HBsAg and HBcAg were contained in the tumor cells and liver cells. HBsAg was found in the nontumorous liver tissue of 30 patients (50%); nine of the HBsAg-containing nontumorous livers also contained HBcAg. HBsAg and/or HBcAg was detected in tumor cells in 7 (23%) of 30 cases with HBsAg-positive liver diseases.
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Objective To discuss the relationship between the expression of HBsAg and HBcAg in the liver tissue and the content of HBV-DNA in serum of patients with chronic hepatitis B. Methods 51 patients with chronic hepatitis B were choose randomly and detected by the content of HBV-DNA,and the expression of HBsAg and HBcAg in liver tissue of the patients.Results There were positive correlation between the expressive intensity of HBcAg in liver tissue and the content of HBV-DNA in serum,the correlation between the expressive intensity of HBsAg in liver tissue and HBV-DNA in serum is feeblish. Conclusion It is more reliable to take the expressive degree of HBsAg and HBcAg in liver tissue combining the content of HBV-DNA in serum as antivirus therapeutical indexes than single one.
HBcAg
Liver tissue
Hepatitis B
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Objective To evaluate the immunogenicity of hepatitis B core antigen(HBcAg)as well as its immunopotentiation to hepatitis B surface antigen(HBsAg).Methods The morphologies of HBcAg,HBsAg and virus-like particles(VLPs)of HBcAg+HBsAg were observed by electron microscopy.Mice were randomly divided into negative control(normal saline,NS),HBcAg(C),HBsAg(S),HBsAg+aluminum adjuvant(S+A)l,HBsAg+HBcAg(S+C)and HBsAg+HBcAg+aluminum adjuvant(S+C+A)l groups,and immunized i.m.with the corresponding antigens on days 0 and 14 respectively,of which the sera were collected and determined for anit-HBs,anti-HBc and antibody subclass against HBsAg.Meanwhile,the splenocytes of mice were collected and determined for IFNγ levels against HBsAg and HBcAg as well as IL-4 level against HBsAg.Results Elec-tron microscopy showed that both HBsAg and HBcAg formed VLPs with uniform structures,while the VLPs of mixed antigen were aggregated.The anti-HBs levels after the first immunization showed no significant difference in S+C and S groups(P = 0.074),while those after the second immunization were significantly higher in S+C group than in S group(P = 0.002).High anti-HBc levels were induced in both C and S+C groups.The antibody subclasses against HBsAg in S group were mainly IgG1,while those in S+C group were mainly IgG2a.The number of spots formed by IFNγ against HBsAg in S+C group was significantly larger than those in S,S+Al and S+C+Al groups(P 0.05).Both the numbers of spots formed by IFNγ against HBcAg were large in C and S+C groups.However,the numbers of spots formed by IL-4 against HBsAg were higher in S+C+Al group than in S+Al group(P = 0.026).Conclusion HBcAg showed good immunogenicity,which enhanced the immune response of HBsAg and promoted the Th1 polarization of the response.It laid a foundation of development of therapeutic HB vaccine.
HBcAg
Hepatitis B vaccine
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Objective To observe the HBsAg and HBcAg expression in the renal tissue in hepatitis B virus associated glomerulonephritis(HBV-GN) . Methods We selected 50 cases of HBV-GN as research group and the other randomly selected 20 cases of non-HBV-GN(NHBV-GN) as control group and used indirect immunofluorescence assay to detect the HBsAg and HBcAg expression in the renal puncture biopsies. Results The HBsAg and HBcAg-positive particles in the HBV-GN renal tissue could be detected,with the positive rates of 70%(35/50) and 24%(12/50) ,while HBsAg and HBcAg failed to be detected in the kidney tissue of 20 cases of NHBV-GN,with a significant difference between the two groups(P0.05) . Conclusion The immune fluorescence detection of HBsAg and HBcAg is an important indicator in the diagnosis of HBV-GN. HBV plays an important role in the kidney tissue infection and replication and the pathogenesis of HBV-GN.
HBcAg
Hepatitis B
Immunofluorescence
Pathogenesis
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