| Abstract: | B型肝炎病毒（hepatitis B virus, HBV）感染可能產生慢性肝炎、肝硬化或肝癌等持久性的慢性疾病。HBV的一種分泌性e蛋白（又稱e抗原，HBeAg）不是病毒的結構性蛋白，但可在感染者的血液中偵測得到。研究者常推測HBeAg可能與HBV的慢性感染有關，但直接的實驗證明闕如，其作用機轉更是不明。本實驗室發現HBe蛋白可與人類周邊血液的中性顆粒細胞 (neutrophil) 及單核細胞（monocyte）結合，並會刺激單核細胞產生第六介白質 (interleukin 6, IL-6)、第八介白質 (interleukin 8, IL-8)、第十介白質 (interleukin 10, IL-10)、第一型單核細胞趨化蛋白 (monocyte che- moattractant protein 1, MCP-1) 及第一型巨噬細胞發炎蛋白 (macrophage inflammatory protein 1, MIP-1等細胞激素（cytokine）或趨化激素(chemokine），HBe蛋白也可以抑制中性顆粒細胞及單核細胞的respiratory burst及活動力 (mobility)，因此我們推測HBe蛋白可能在HBV感染時扮演一個改變宿主先天性免疫機能的角色。 為了進一步探討HBe蛋白的功能，我們希冀利用動物模式進行機制的研究及in vivo的實驗。由於HBe蛋白的DNA序列在人類HBV、土撥鼠 (woodchuck) 肝炎病毒及地松鼠 (ground squirrel) 肝炎病毒中均相當地conserved，因此我們假設HBe可能會對各種哺乳類動物的細胞都有影響力。由於小鼠的品系及試劑眾多，基因轉植技術完善，所以希望能利用小鼠做為實驗模式。經試驗後，我們果真證實HBe可以與小鼠的巨噬細胞及B淋巴細胞結合，但不與T淋巴細胞結合。HBe也可以誘導巨噬細胞激素之分泌。除此之外，我們也已生產 HBe基因轉殖小鼠。未來將可利用小鼠模式，探討HBe蛋白在in vitro對小鼠抗原呈現細胞 (antigen-presenting cells, APC)及B淋巴細胞的影響。除了進行in vitro的免疫功能試驗之外，也可利用本實驗室生產的HBe轉殖小鼠，探討在HBe的存在下，小鼠對抗外來抗原之免疫反應是否發生變化。這些研究將會使我們更加明瞭HBe在HBV與宿主的相互作用中扮演的角色。
Hepatitis B virus may cause chronic liver diseases such as chronic hepatitis B, liver cirrhosis or/and hepatocellular carcinoma. A secretory protein encoded by HBV, the HBe protein or HBeAg, is not present in viral particles and is not essential for HBV replication. It has been suggested that HBe is involved in the persistent infection. However, the role of HBe protein may play in chronic infection is unclear. We previously demonstrated that HBe protein bound to human blood neutrophils, monocytes, B lymphocytes, but not T lymphocytes. It could induce the production of interleukin 6 (IL-6), IL-8, IL-10, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 (MIP-1) ?from monocytes. The mobility and the respiratory burst were also suppressed in neutrophils and monocytes after treatment of HBe protein. These findings made us hypothesize that HBe protein may be a viral immunomodulatory factor. We then attempted to establish an animal model to study the functions of HBe protein. Since the HBe protein is conserved among human HBV, woodchuck hepatitis B virus and ground squirrel hepatitis B virus, we hypothesize that a conserved HBe-binding protein (or “receptors”) may also be conserved among mammals, including the mouse. Our results indeed proved that HBe protein could bind to mouse macrophages, dendritic cells, B lymphocytes, but not T lymphocytes. In the future, we will investigate whether HBe protein would affect the functions of antigen-presenting cells, B lymphocytes and/or T lymphocytes indirectly in vitro. Furthermore, we will investigate whether the immune responses against foreign antigens, e.g., HBsAg and ovalbumin (OVA), would be modulated in the presence of HBe protein in mice. To study this, the HBe-transgenic mice which were produced by us will beused. These studies will shed light on how HBe protein functions in the HBV-host interaction. |
