State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Hepatobiliary Pancreat Dis Int. 2010 Dec;9(6):584-92.
Hepatitis B virus (HBV) is a hepatotropic, noncytopathic, DNA virus which can cause acute and chronic infection. Viral persistence is associated with a weak or absent specific immune responses to HBV, particularly the cellular immune response. Dendritic cells (DCs) are professional antigen-presenting cells with a unique T cell stimulatory aptitude that play a crucial role in the instruction of adaptive immune responses upon infection. An impaired function of DCs was suggested by recent studies to account for the T and B cell hyporesponsiveness in chronic HBV infection. This review summarizes recent insights into the recognition of HBV antigens by DCs.
Studies were identified by searching MEDLINE and/or PubMed for articles using the key words "hepatitis B virus (HBV)", "dendritic cells", "C-type lectins", "mannose receptor", "toll-like receptor", and "dendritic cell-specific intercellular-adhesion-molecule-3 grabbing nonintegrin (DC-SIGN)" up to December 2009. Additional papers were identified by a manual search of the references from the key articles.
DCs play an important role in the progress of hepatitis B, especially in the recognition of HBV. There are three main ways of recognition of HBV antigens by DCs. First, HBV DNA can be recognized by DCs through toll-like receptor 9 (TLR9) which activates the NF-κB signal pathway and p38 MAPK to up-regulate the expression of interferon (IFN) regulatory factor 7 (IRF-7) in a manner independent of type I IFN signaling, resulting in secretion of type I IFN and inflammatory cytokines, and induction of DC maturation and the adaptive immune response. Second, HBc/HBeAg cannot be recognized by DCs, but DNA or ssRNA encapsulated within HBcAg can be internalized by DCs through TLRs. Third, HBsAg can be internalized by DCs through the mannose receptor, which lacks the ability to induce DC maturation without the assistance of DC-SIGN. Meanwhile, there is some cross-talk among the three mechanisms, which induces an effective anti-viral response or HBV persistence.
On the basis of these recognition processes, methods have been used to enhance the efficacy of DC-based vaccine against HBV and have been useful in the clinical application of HBV vaccine therapy. But the interactions between HBV antigens/HBV DNA and DCs are not clear, and cross-talk between TLRs and various ligands makes HBV antigen recognition by DCs more complicated. More efforts should be made to define the mechanisms and develop effective vaccines and therapies.
乙型肝炎病毒（HBV）是一种嗜肝、非致细胞病变的 DNA 病毒，可引起急性和慢性感染。病毒持续存在与对 HBV 的弱或不存在特异性免疫反应有关，特别是细胞免疫反应。树突状细胞（DC）是具有独特的 T 细胞刺激能力的专业抗原呈递细胞，在感染时对适应性免疫反应的指导中起着至关重要的作用。最近的研究表明，DC 的功能受损是导致慢性 HBV 感染中 T 和 B 细胞反应低下的原因。本综述总结了最近对 HBV 抗原被 DC 识别的认识。
通过在 MEDLINE 和/或 PubMed 中搜索使用关键词“乙型肝炎病毒（HBV）”、“树突状细胞”、“C 型凝集素”、“甘露糖受体”、“Toll 样受体”和“树突状细胞特异性细胞间黏附分子-3 抓取非整合素（DC-SIGN）”来确定研究。截至 2009 年 12 月，还通过对关键文章的参考文献进行手动搜索确定了其他论文。
DC 在乙型肝炎的进展中起着重要作用，特别是在识别 HBV 方面。DC 识别 HBV 抗原有三种主要方式。首先，HBV DNA 可通过 Toll 样受体 9（TLR9）被 DC 识别，TLR9 通过 NF-κB 信号通路和 p38 MAPK 激活来上调干扰素（IFN）调节因子 7（IRF-7）的表达，这种方式不依赖于 I 型 IFN 信号，导致 I 型 IFN 和炎症细胞因子的分泌，并诱导 DC 成熟和适应性免疫反应。其次，HBc/HBeAg 不能被 DC 识别，但 DNA 或 ssRNA 包裹在 HBcAg 内可被 TLR 内吞。第三，HBsAg 可通过甘露糖受体被 DC 内吞，甘露糖受体缺乏诱导 DC 成熟的能力，而无需 DC-SIGN 的辅助。同时，这三种机制之间存在一些串扰，从而诱导有效的抗病毒反应或 HBV 持续存在。
基于这些识别过程，已经使用了一些方法来提高基于 DC 的 HBV 疫苗的功效，并在 HBV 疫苗治疗的临床应用中取得了一定的效果。但是，HBV 抗原/HBV DNA 与 DC 之间的相互作用并不清楚，TLRs 与各种配体之间的串扰使 DC 对 HBV 抗原的识别更加复杂。应进一步努力阐明这些机制，并开发有效的疫苗和疗法。
