B型肝炎病毒e蛋白對淋巴細胞增殖之影響

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Title:	B型肝炎病毒e蛋白對淋巴細胞增殖之影響
Other Titles:	Effect of hepatitis B virus e protein on the proliferation of lymphocytes
Authors:	李宇翔 Lee, Yu-Hsiang
Contributors:	胡承波 Hu, Cheng-Po 東海大學生命科學系
Keywords:	B型肝炎病毒;e蛋白;淋巴細胞增殖 Hepatitis B virus;e protein;lymphocyte proliferation
Date:	2008
Issue Date:	2011-03-24T05:35:05Z (UTC)
Abstract:	B型肝炎病毒 (hepatitis B virus, HBV) 感染為全球性的嚴重健康問題，每年有一百萬人死於慢性B型肝炎引起的肝硬化、肝癌或肝臟衰竭。形成HBV慢性感染的原因可能與病毒干擾宿主免疫反應的能力有關，但其真正機轉至今未明。HBV的e (HBe) 蛋白為一非結構性蛋白質，與病毒的感染和複製能力無直接關聯，但所有的嗜肝DNA病毒(hepadnavirus)都表現HBe蛋白，因此HBe蛋白可能在HBV與宿主間之相互關係中扮演重要的角色。本實驗室過去發現HBe蛋白可與人類及小鼠的單核細胞及巨噬細胞結合，並影響細胞激素分泌、趨化作用及過氧化物之產生。巨噬細胞除了執行先天性免疫反應之外，亦具有呈獻抗原 (antigen presentation) 的功能，繼而刺激T細胞活化。本實驗室過去亦發現HBe蛋白不只和巨噬細胞結合，亦可與人類及小鼠B淋巴細胞結合，因此，本研究想探討HBe蛋白對淋巴細胞的影響。結果顯示HBe蛋白在試管中(in vitro)可微幅刺激小鼠脾臟細胞分裂，在以carboxyfluorescein diacetate, succinimidyl ester (CFSE)及B220抗體雙重染色的觀察下，HBe蛋白對B淋巴細胞具有促進分裂之作用。至於HBe蛋白對T淋巴細胞的影響上，不論以純化之CD8+或CD4+ T細胞進行細胞分裂實驗或以整體T細胞藉由雙重染色測定CD8+或CD4+ T細胞之增生，都發現沒有作用。最後在T細胞受體基因轉殖小鼠OT-1的CD8+ T細胞中亦沒有發現HBe蛋白會影響抗原引發的特異性T細胞增生。本研究之初步結果顯示HBe蛋白可能會增加B細胞的增生，但對T細胞則沒有作用。由於本實驗室過去曾發現HBe蛋白可與B細胞結合，是否HBe蛋白的確在結合B淋巴細胞後繼而影響其功能，尚待進一步研究確認。 Hepatitis B virus (HBV) infection is a global public health problem. Approximately one million people die from HBV-related liver cirrhosis and hepatocellular carcinoma every year. In order to persist in the host, HBV may have immunomodulatory abilities to interfere the host immune response. However, the mechanism of chronicity of HBV infection is still unknown. The hepatitis B viral e (HBe) protein is a non-structural protein. It is not present in the virion and not required for infection or replication of HBV. However, the HBe protein is conserved in all members of hepadnaviruses, suggesting that it may play an important role in HBV-host interactions. Our laboratory has previously found that the HBe protein binds to human and mouse monocytes and macrophages. Furthermore, it modulates chemotaxis and the production of peroxides and cytokines. In addition to participate in innate immune functions, macrophages also present antigens to T lymphocytes, leading to T cell activation and proliferation. Our laboratory has also found that the HBe protein could bind to human and mouse B lymphocytes. Therefore, the purpose of this thesis was to investigate the effect of the HBe protein on lymphocytes. I found that HBe could slightly induce mouse splenocyte proliferation in vitro. Using double labeling with carboxyfluorescein diacetate, succinimidyl ester (CFSE) and B220 antibody, I found that HBe could induce B cell proliferation. By contrast, the HBe protein had no effect on the proliferation of CD3+, CD8+ or CD4+ T cells which were cross-linked by anti-CD3/anti-CD28 antibodies. Finally, the effect of HBe on antigen-specific T cells was studied using CD8+ T cells of OT-I TCR-transgenic mice. My preliminary results did not show any effect of HBe on OVA peptide-induced T cell proliferation. Thus, the HBe protein seems to stimulate the proliferation of B cells but not T cells. How the proliferative signal is delivered after the binding of HBe on B cells remains to be investigated.
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