Various findings concerning the clinical significance of quantitative changes in hepatitis B surface antigen (HBsAg) during the acute and chronic phase of hepatitis B virus (HBV) infection have been reported. In addition to being a biomarker of HBV-replication activity, it has been reported that HBsAg could contribute to the immunopathogenesis of HBV persistent infection. Moreover, HBsAg could become an attractive target for immune therapy, since the cellular and humeral immune response against HBsAg might be able to control the HBV replication and life cycle. However, several reports have described the immune suppressive function of HBsAg. HBsAg might suppress monocytes, dendritic cells (DCs), natural killer (NK), and natural killer T (NK-T) cells by direct interaction. On the other hand, cytotoxic T lymphocytes (CTLs) and helper T (Th) cells were exhausted by high amounts of HBsAg. In this paper, we focused on the immunological aspects of HBsAg, since better understanding of the interaction between HBsAg and immune cells could contribute to the development of an immune therapy as well as a biomarker of the state of HBV persistent infection. 1. Introduction Hepatitis B virus (HBV) is basically a noncytopathic DNA virus that causes chronic hepatitis and hepatocellular carcinoma (HCC) as well as acute hepatitis and fulminant hepatitis [1]. HBV now affects more than 400 million people worldwide and, in approximately 5% of adults and 95% of neonates who become infected with HBV, persistent infection develops [2]. HBV contains a small (3.2？kb), circular, partially double-strand DNA organized into four open-reading frames. The longest open-reading frame encodes the viral polymerase. The envelope open-reading frame is located within the polymerase open-reading frame in a frame-shift manner. The core and X open-reading frames partially overlap with the envelope open-reading frame [3, 4]. The covalently closed circular DNA (ccc DNA) is the template that is transcribed to generate four major RNA species: the 3.5？kb, 2.4？kb, 2.1？kb, and 0.7？kb viral RNA transcripts [5]. HBV produces Hepatitis B core antigen (HBcAg), Hepatitis B envelope antigen (HBeAg), Hepatitis B X antigen (HBxAg), and Hepatitis B surface antigen (HBsAg) that could contribute to the HBV life cycle. HBsAg was found by Blumberg et al. in 1965 and regarded as an HBV-related antigen in 1968 [6, 7]. The clinical significance of quantitative changes in HBsAg during the acute and chronic phase of HBV infection has been reported [8–10]. The amount of HBsAg has been found to be closely related to the
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