Hepatitis B Virus Core Antigen Binds and Activates Naive Human B Cells In Vivo: Studies with a Human PBL-NOD/SCID Mouse Model

Abstract

The hepatitis B virus (HBV) core (HBc) antigen (HBcAg) is a highly immunogenic subviral particle. Studies with mice have shown that HBcAg can bind and activate B cells in a T-cell-independent fashion. By using a human peripheral blood leukocyte (hu-PBL)-Nod/LtSz-Prkdc scid /Prkdc scid (NOD/SCID) mouse model, we show here that HBcAg also activates human B cells in vivo in a T-cell-independent way. HBcAg was capable of inducing the secretion of HBcAg-binding human immunoglobulin M (IgM) in naive human B cells derived from adult human and neonatal (cord blood) donors when these hu-PBL were transferred directly into the spleens of optimally conditioned NOD/SCID mice. No such responses were found in chimeric mice that were given hu-PBL plus HBV e antigen or hu-PBL plus phosphate-buffered saline. In addition, HBcAg activated purified human B cells to produce anti-HBc IgM in the chimeric mice, thus providing evidence that HBcAg behaves as a T-cell-independent antigen in humans. However, HBcAg-activated hu-PBL from naive donors were unable to switch from IgM to IgG production, even after a booster dose of HBcAg. Production of HBcAg-specific IgG could only be induced when hu-PBL from subjects who had recovered from or had an ongoing chronic HBV infection were transferred into NOD/SCID mice. Our data suggest that humans also have a population of naive B cells that can bind HBcAg and is subsequently activated to produce HBcAg-binding IgM.

A fusion product of the complete Borrelia burgdorferi outer surface protein A (OspA) and the hepatitis B virus capsid protein is highly immunogenic and induces protective immunity similar to that seen with an effective lipidated OspA vaccine formula

“…Moreover, recent data indicate that HBcAg can also bind to and activate B cells via a linear motif present in the FR1-CDR1 junction of the heavy or light chain of the B cell surface receptor [26]. The latter process may also lead to the induction of co-stimulatory molecules required for efficient priming of Th cells [28,29].…”

“…Moreover, HBcAg directly binds to and activates a large fraction of naive B cells [25], both murine and human, via linear conserved regions of the Ig heavy and light chains [26]. Finally, HBcAg expresses multiple Th epitopes for CD4 + T cells [27][28][29].…”

Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent

“…The capsid is composed of 180 or 240 copies of the 21 kDa core protein and exhibits hepatitis B virus core antigenicity (HBcAg). HBcAg is a unique immunogen and functions as both a T cell-independent and a T cell-dependent antigen in mice and humans (Cao et al, 2001;Milich & McLachlan, 1986). The immunogenicity of HBcAg has been proposed to rely on its structural properties (Fehr et al, 1998;Milich & McLachlan, 1986;Schodel et al, 1996).…”

“…The region on HBcAg involved in binding to sIg on naive B cells has not been mapped. HBcAg binds directly to a large proportion of naive human and mice B cells through this non-traditional antigen-antibody interaction (Cao et al, 2001;Lazdina et al, 2001a;Milich et al, 1997). The B cells become activated upon BCR cross-linking by HBcAg, as evidenced by an increase in the surface expression of B7-2 (Lazdina et al, 2001a;Milich et al, 1997).…”

Core mutations in patients with acute episodes of chronic HBV infection are associated with the emergence of new immune recognition sites and the development of high IgM anti‐HBc index values

“…It can therefore be presumed that the binding affinity of IgM anti-HBc changes depending on conformational changes of the epitope that may occur during the course of chronic hepatitis, culminating consequently in new antibody production. Cao et al [2001] developed an animal model similar to humans and showed that HBcAg directly activated B cells and induced IgM anti-HBc production in a T-cell independent fashion. Moreover, naïve B cells produced capsid-binding IgM, when co-cultured with very low levels of capsids and T-cells from HBcAg-specific T cell receptor transgenic mice .…”