【作者】 王沂芹；

【导师】 吴玉章；

【作者基本信息】 第三军医大学 ， 免疫学， 2006， 博士

【摘要】 慢性乙型肝炎(chronic hepatitis B,CHB)危害严重,是肝癌、肝硬化的首要病因。2005年,慢性乙型肝炎被列为我国四大重点防治的传染病之一。明确乙型肝炎病毒(hepatitis B virus,HBV)持续感染的免疫病理机制,对慢性乙型肝炎的防治至关重要。HBV特异性CD8+ T细胞,即细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)介导的免疫应答在病毒清除过程中起主导作用;HBV特异性CTLs功能低下是慢性乙型肝炎病毒持续感染的关键原因。探讨HBV特异性CTLs功能低下的机制是研究的焦点。在慢性乙型肝炎研究中发现,患者的HBV特异性CTLs在体外给予抗原肽刺激后不能增殖或增殖能力下降;而急性自限性乙型肝炎患者以及恢复期患者的HBV特异性CTLs在体外给予抗原肽刺激后可以迅速增殖,分泌细胞因子并行使其效应功能。克隆扩增是淋巴细胞最基本的功能,抗原特异性CTLs增殖的同时获得效应功能,CTLs的增殖能力是病原体能否清除的关键。因此慢性乙型肝炎患者HBV特异性CTLs增殖能力下降是其功能低下的关键。然而,慢性乙型肝炎患者HBV特异性CTLs不能增殖或增殖能力下降的原因并没有进一步的研究报道。T细胞增殖老化(replicative senescence)是指细胞有新陈代谢,但是增殖能力下降或不能进一步增殖。老化T细胞的首要特点是:细胞增殖能力下降、CD28表达缺失。老化T细胞还具有以下重要特点:(1)细胞表面表达自然杀伤细胞相关受体(natural killer-associated receptors, NKRs),如CD56、CD57、杀伤细胞抑制性受体(killer inhibitory receptor, KIR); (2)细胞对凋亡耐受;(3)细胞多处于分化晚期或终末期;(4)老化T细胞效应功能低下。T细胞增殖老化是正常人体老化的一部分,是老年人免疫功能低下的重要原因。然而T细胞增殖老化的过程与年龄无关,因为它是根据T细胞增殖历史而不是人的寿命命名的。研究表明抗原持续存在引起的免疫活化,迅速导致病毒特异性CTLs老化。在年轻的慢性炎症、持续感染患者体内能够发现老化的T细胞,与患者的年龄不相符,并且这群细胞与疾病的严重程度密切相关,它们的存在和意义正引起人们的更多还原

【Abstract】 More than 400 million people worldwide are persistently infected with the hepatitis B virus (HBV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. The ability to clear HBV after infection has been associated with the presence of a strong HBV-specific cytotoxic T lymphocytes (CTLs) response. However, the main immunological feature that characterizes chronically infected patients is a state of relative hyporesponsiveness of HBV-specific CTLs compared with that demonstrable in acute self-limited hepatitis B patients.HBV-specific CTLs of chronic hepatitis B (CHB) patients couldn’t expand when stimulated with antigen peptides in vitro, while HBV-specific CTLs of acute self-limited hepatitis B patients and resolved patients could expand vigorously. The difference in peptide induced CTLs proliferation has not been explained till now. Clone expanding is the fundamental function of T lymphocytes. During persistent infections, the principal determining viral control has been suggested to be the ability of virus-specific CTLs to clonally expand, and the antiviral effector functions are always coupled with clonally expand. So elucidating the reason why HBV-specific CTLs of CHB patients couldn’t expand may be the key to explain the hyporesponsiveness of HBV-specific CTLs.Studies have suggested that chronic stimulation can result in the development of specific CTLs that are incapable of cell division. Such a failure to proliferate is generally attributed to replicative senescence. The key feature of senescent T cells is the loss of CD28, the dominant costimulatory receptor required for the induction and maintenance of T-cell-mediated immunity. Senescent T cells also possess other features: these cells express a variety of natural killer-associated receptors (NKRs) and are resistant to apoptosis, most更多还原