臺灣博碩士論文加值系統

B型肝炎病毒的感染會導致急性或慢性肝炎,而慢性肝炎病毒。的帶原者有很高的機率會演變成肝硬化或是肝癌。在演化的過程中,病毒發展出其特殊的方式來入侵宿主的免疫系統,以達到慢性感染的目的.B型肝炎病毒的e抗原不存在於病毒顆粒當中,和病毒的感染力與複製也沒有直接的關聯,所以被認為可能和干擾宿主的免疫反應有關係。Kupffer細胞是肝臟內的巨噬細胞,不但具有呈現抗原(antigen presentation)的功能,也被認為與肝臟內免疫反應的調控有關.本研究證明e抗原可和小鼠的Kupffer細胞結合,並且也發現e抗原可以誘使小鼠Kupffer細胞產生細胞激素IL-1, IL-6, IL-10, TNF-alpha, TGF-beta, MIP-2及MCP-1。其次我們想瞭解是否e抗原會影響T細胞的功能及抗體的產生。在利用植物血凝素(phytohemagglutinin)刺激T細胞增生的實驗中,我們發現e抗原會使Kupffer細胞呈現抗原的能力降低。在小鼠對抗B型肝炎病毒表面抗原的實驗中顯示,e抗原並不會影響對抗HBsAg的總IgG量,但是卻明顯地抑制了對抗HBsAg的IgG2a 。綜合以上結果,e抗原可以誘發Kupffer細胞產生細胞激素及改變宿主的T細胞及抗體反應功能,藉由此功能可能可以助長病毒的潛伏及慢性感染。

Hepatitis B virus (HBV) is a hepatotropic, noncytopathic virus that causes acute and chronic necroinflammatory liver diseases. Chronic HBV carriers serve as a source for new infections and are at a high risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). To establish a chronic infection, viruses have developed strategies to evade host immune system. HBeAg is not a structural component of the HBV, nor is required for the viral infectivity and replication. It may play an immunomodulatory role in the life cycle of HBV. Kupffer cells are the resident macrophages in the liver and can function as antigen-presenting cells. It has been suggested that Kupffer cells are involved in the regulation of intrahepatic immune responses. To study if HBeAg may modulate the function of Kupffer cells and further affect host anti-HBV immunity, we examined the interaction between HBeAg and Kupffer cells and further investigated the effect of HBeAg on T cell proliferation and antibody production. Dual-color flow cytometric analysis showed that HBeAg could bind to Kupffer cells, and HBeAg was able to trigger the expression of IL-1, IL-6, IL-10, TNF-alpha, TGF-beta, MIP-2, and MCP-1 in Kupffer cells. In the present study, we also showed that HBeAg decreased the antigen presenting ability of Kupffer cells in a PHA-stimulated T cell proliferation assay. Furthermore, we showed that the amount of anti-HBs IgG2a was significantly decreased in HBeAg-treated mice although the total anti-HBs IgG was the same in HbeAg-treated and control mice. Taken together, our results suggest that HBeAg may modulate the function of Kupffer cells and then modify the anti-HBV immune responses. These effects may result in ineffective viral clearance and establishment of persistent infection.

中文摘要 1
Abstract 2
Introduction 3
Materials and Methods 9
Results 26
Discussion 35
Reference 43
Fig1. Open reading frames of HBV genome.
Fig2. The biogenesis of HBeAg and HbcAg from HBV precore/core ORF.
Fig3. The alignment of HBeAg derived from hepadnaviruses.
Fig4. The sinusoidal endothelial cells and Kupffer cells line the hepatic sinusoids.
Fig5. Purification of recombinant HBeAg.
Fig6. Sequence of HBeAg (ayw) used for the construction of pCMV-HBe plasmid.
Fig7. Construction of pCMV-HBe plasmid.
Fig8. Production of HBeAg from 293T cells.
Fig9. Characterization of 293T-expressed HBeAg by Western blottin using anti-HBc antibody.
Fig10. Purification of 293T-expressed HBeAg.
Fig11. Identification of Kupffer cells.
Fig12. Flow cytometric analysis.
Fig13. Flow cytometric analysis.
Fig14. Analysis of purified Kupffer cells by flow cytometry.
Fig15. HBeAg binds to Kupffer cells.
Fig16. HBeAg binds to Kupffer cells.
Fig17. Expression of IL-1b and MIP-2 genes in freshly isolated Kupffer cells.
Fig18. The morphology of cultured Kupffer cells.
Fig19. The activity of 293T-expressed HBeAg.
Fig20. Induction of cytokine and chemokine genes by HBeAg in Kupffer cells at mRNA level.
Fig21. The iNOS protein was not induced by HBeAg in Kupffer cells.
Fig22. HBeAg did not induce nitrite production in PECs.
Fig23. Enhancement of IL-6 production in Kupffer cells after HBeAg treatment.
Fig24. Enhancement of MCP-1 in Kupffer cells after HBeAg treatment.
Fig25. Decrease of HBeAg-induced IL-6 production in PEC by anti-HBc antibody.
Fig26. Purified HBeAg induced the production of IL-6 in Kupffer cells.
Fig27. Purification of splenic T cells.
Fig28. PHA-induced T cell proliferation using Kupffer cells as antigen-presenting cells.
Fig29. Effect of HBeAg in PHA-induced T cell proliferation using Kupffer cells as antigen-presenting cells.
Fig30. HBeAg inhibits PHA-induced T cell proliferation.
Fig31. Effect of HBeAg on the production of anti-HBs antibodies.
Fig32. Effect of HBeAg on the production of anti-HBs IgG1 and IgG2a.
Fig33. Hypothesis of the immunomodulatory function of HBeAg during early HBV infection.

Content
中文摘要………………………………………………………………………………1
Abstract……………………………………………………………………………….2
Introduction…………………………………………………………………………3
Materials and Methods……………………………………………………………9
Results……………………………………………………………………………..26
Discussion…………………………………………………………………………35
Reference………………………………………………………………………….43
Fig1. Open reading frames of HBV genome.
Fig2. The biogenesis of HBeAg and HbcAg from HBV precore/core ORF.
Fig3. The alignment of HBeAg derived from hepadnaviruses.
Fig4. The sinusoidal endothelial cells and Kupffer cells line the hepatic sinusoids.
Fig5. Purification of recombinant HBeAg.
Fig6. Sequence of HBeAg (ayw) used for the construction of pCMV-HBe plasmid.
Fig7. Construction of pCMV-HBe plasmid.
Fig8. Production of HBeAg from 293T cells.
Fig9. Characterization of 293T-expressed HBeAg by Western blottin using anti-HBc antibody.
Fig10. Purification of 293T-expressed HBeAg.
Fig11. Identification of Kupffer cells.
Fig12. Flow cytometric analysis.
Fig13. Flow cytometric analysis.
Fig14. Analysis of purified Kupffer cells by flow cytometry.
Fig15. HBeAg binds to Kupffer cells.
Fig16. HBeAg binds to Kupffer cells.
Fig17. Expression of IL-1b and MIP-2 genes in freshly isolated Kupffer cells.
Fig18. The morphology of cultured Kupffer cells.
Fig19. The activity of 293T-expressed HBeAg.
Fig20. Induction of cytokine and chemokine genes by HBeAg in Kupffer cells at mRNA level.
Fig21. The iNOS protein was not induced by HBeAg in Kupffer cells.
Fig22. HBeAg did not induce nitrite production in PECs.
Fig23. Enhancement of IL-6 production in Kupffer cells after HBeAg treatment.
Fig24. Enhancement of MCP-1 in Kupffer cells after HBeAg treatment.
Fig25. Decrease of HBeAg-induced IL-6 production in PEC by anti-HBc antibody.
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Billar, TR., Curran, RD. (1992) Hepatocyt and Kupffer cell interactions.
Blumberg, B. S. (1997). The current state of the prevention of HBV infection, the carrier state and hepatocellular carcinoma. Res Virol 148, 91-4.
Campbell, J. D., and HayGlass, K. T. (2000). T cell chemokine receptor expression in human Th1- and Th2-associated diseases. Arch Immunol Ther Exp (Warsz) 48, 451-6.
Chang, C., Enders, R., Sprengel, N.,Peters, HE. Varmus, Ganmen, D (1987). Expression of the precore region of an abian hepatitis B virus is not required for viral replication. J. Virol. 61, 3322-29.
Chang, K. (1999). The effects of HBcAg and HBeAg on the expression of cytokine genes from murine macrophages. In Institute of microbiology and immunology: National yang-ming university, school of life science).
Chen, A. (2000). The effects of the Hepatitis B virus e antigen on macrophages and lymphocytes. In Institute of microbiology and immunology: national yang-ming university, school of life science).
Chen, H., Kew MC., Hornbuckle WE., Tennant BC., Cote PJ., Gerin JL., Purcell RH., Miller RH. (1992). The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host. Journal of virology 66, 5682-84.
Chow, YH., Huang, WL., Chi, WK., Chu, YD., Tao, MH. (1997). Improvement of Hepatitis B virus DNA vaccines by plasmids coexpressing Hepatitis B surface antigen and IL-2. Journal of immunology 71,168-78
Chow, YH., Chiang, BL., Lee, YL., Chi, WK., Lin, WC., Chen, YT., Tao, MH. (1998). Development of Th1 and Th2 populations and the nature of immune responses to Hepatitis B virus DNA vaccines can be modulated by codelivery of various cytokine genes. Journal of immunology, 160, 1320-29
Coffman, R. L. (1989). Cytokine regulation of immunolglobulin isotype switching and expression. Semin. Immunol 1, 55.
Crispe, I. N., Dao, T., Klugewitz, K., Mehal, W. Z., and Metz, D. P. (2000). The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev 174, 47-62.
Decker, K. (1990). Biologically active products of stimulated liver macrophages (Kupffer cells). Eur. J. Biochem. 192, 245-61.
Diefenbach, A. (1998). Type 1 infection (TNF alpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to protozoan parasites. Immunity 8, 77-87.
Doherty, D., O'Farrelly, C. (2000). Innate and adaptive lymphoid cells in the human liver. Immunolgical reviews 174, 5-20.
Flesch, B. K. Neppert, J. (2000). Functions of the Fc receptors for immunoglobulin G. J Clin Lab Anal 14(4) 141-56
Finkelman, F. D. (1988). IFN-gamma regulates the isotypes of Ig secreted during in vivo humoral immune responses. Journal of immunology 140, 1022.
Finkelman, F. D. (1990). Lymphokine control of in vivo immunoglobulin isotype selection. Annu. Rev. Immunol. 8, 303.
Franco, M., Greenberg, HA. (1995). Role of B cells and cytotoxic T lymphocytes in clearance of and immunity to rotavirus infection in mice. Journal of virology 69 (12), 7800-6.
Galle, P. R., Hofmann, W. J., Walczak, H., Schaller, H., Otto, G., Stremmel, W., Krammer, P. H., and Runkel, L. (1995). Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med 182, 1223-30.
Gerken, P. K. G. (2000). Local control of the immune response in the liver. Immunological review 174, 21-34.
Goerdt, S., Orfanos, CE. (1999). Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10, 137-42.
Gooding, L. R. (1997). Virus protines that conteract host immune defenses. Cell 71, 5-7.
Gregory, S., Wind, EJ. (1998). Neutrophil-Kupffer cell interaction in host defenses to systemic infections. Immunology today 19(11), 507-10.
Gu, L., Tseng S, Horner RM, Tam C, Loda M, Rollins BJ. (2000). Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 23;404(6776), 407-11.
Huang, L., Soldevila, G., Leeker, M., Flavell, R., Crispe, IN. (1994). The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1, 741-63.
Kalvakolanu, D. (1999). Virus interception of cytokine-regulated pathways. Trends in Microbiol. 7, 166-71.
Katayama, M. H., T. Takehara, Y. Kawanishi, A. Kasahara, H. Fusamoto, T. Kamada (1994). Effects of Hepatitis B virus antigens on interferon-gamma production of peripheral blood mononuclear cells from hepatitis B virus carrier and healthy individuals. Scand J Gastroenterol 29, 849-53.
Khanna, A., Morelli, AE., Zhong, C., Takayama, T., Lu, L., Thomson, AW. (2000). effects of liver-derived dendritic cell progenitors on Th1- and Th2-like cytokine responses in vitro and in vivo. Journal of immunology 164, 1346-1354.
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