ABSTRACT

The way that HBcAg interacts with the host immune system has resulted in a signicant number of papers. It was early recognized that patients infected by the hepatitis B virus (HBV) developed high levels of antibodies to HBcAg (antiHBc) [1]. Early in the acute phase, high levels of anti-HBc IgM appear and have become the gold standard for diagnosing acute HBV [2]. The anti-HBc levels are very high, being one of the rst signs of the immunogenicity of HBcAg, early in the infection, and then wane within a 6-month period [3]. However, in the chronic infection, extremely high levels of anti-HBc IgG appear, again supporting the immunogenicity of HBcAg. One of the early explanations of the high immunogenicity of HBcAg was suggested by Milich and McLachlan in 1986, where they showed that HBcAg was both T-cell-dependent and T-cell-independent antigens [4]. Albeit the role of the T cell independence of HBcAg in the immunogenicity of HBcAg is unclear, this led to two additional discoveries. First, extracellular HBcAg uses the B cell as the primary APC [5]. Second, this was later explained by the fact that HBcAg has the ability to bind naive human [6] and murine [7] B cells through the B cell receptor (BCR) (Figure 14.1). The structure of the latter interaction was recently solved [8]. Importantly, one of the key adjuvant effects seems to be that the HBcAg particles, or proteins, bind single-stranded RNA, which in turn activates the innate Toll-like receptor TLR-7 signaling pathways [9,10]. Thus, it is likely that the HBcAg particles will both cross-link BCRs to induce an activated state in the B cells, and after uptake, the TLR-7 pathway is induced by encapsidated RNA (Figure 14.1). The origin of

the encapsidated RNA in recombinantly produced HBcAg particles seems to be of the origin from the cell where the capsids were expressed. Thus, the capsids seem to contain heterologous RNA [10].