The Multiple Functions of B Cells in Chronic HBV Infection

Abstract

Chronic hepatitis B virus (HBV) infection is one of the main causes of liver diseases, of which the natural history and clinical outcomes are associated with the role of B cells. As humoral immune cells, B cells play a critical role in the process of anti-HBV antibody production. In addition, some studies have also characterized other B cell subsets involved in antigen presentation and regulating the immune response beyond antibody secretion. However, not all B cell subsets play a positive role in the immune response to chronic HBV infection, and various B cell subsets jointly mediate persistent HBV infection, tolerance, and liver damage. Thus, we further sought to elucidate the multiple functions of B cells to gain novel insight into the understanding of chronic hepatitis B (CHB) pathogenesis. We also reviewed the current immunotherapies targeting B cells to explore novel therapeutic interventions for the treatment of chronic HBV infection.

Keywords: B cell; antibody production; antigen presentation; hepatitis B virus; immune regulation; immunotherapy.

Figure 1

Antibody production by B cells and antibody-mediated immune response in CHB infection. B cells can produce antibodies, such as anti-HBs, anti-HBc and self-antibodies, and subsequently mediate an antiviral immune response or self-reaction via various potential mechanisms in CHB infection. (1) Anti-HBs antibodies bind to HBsAg to block viral entry and replication; (2) anti-HBs antibodies bind HBsAg and induce cellular phagocytosis of Kupffer cells to consume HBV (ADCP); (3) anti-HBs antibodies bind HBsAg and induce the release of perforin/granzyme in NK cells to eliminate HBV-infected hepatocytes (ADCC); (4) anti-HBs antibodies participate in forming immune complexes and bind to dendritic cells to induce a T cell response; (5) anti-HBc IgG binds HBcAg to induce hepatocyte lysis via the classical complement activation pathway initiating from C1 (CDC); (6) self-antibodies participate in an autoimmune reaction to aggravate liver inflammation. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CDC, compliment-dependent cytotoxicity.

Figure 2

Antigen presentation function of B cells in CHB infection. The BCR specifically recognizes and binds HBV antigens that exist alone or are presented on the surface of macrophages or dendritic cells. The engagement enables BCR-antigen internalization into endosomes. Concomitant with receptor-mediated endocytosis, MHC-I/MHC-II molecules produced by B cells converge to form complexes with the HBcAg/HBsAg peptides processed in lysosomes and transferred to the plasma membrane. Naive CD4+ T cells are activated by B cells presenting HBcAg-MHC-II complexes, inducing a CD4+ T cell immune response. In addition, CD8+ T cells are activated by B cells presenting HBcAg/HBsAg-MHC-I complexes, inducing CTL cytotoxic reaction. However, the process promotes the apoptosis of HBsAg-infected cells (including HBsAg-infected B cells) and persistent HBV infection. BCRs, B cell antigen receptors; MHC-I, major histocompatibility complex class I; MHC-II, major histocompatibility complex class II.

Figure 3

Immune regulation and antiviral function of B cells in CHB infection. B cells play potential immune regulatory roles to induce or inhibit the immune response via secreting different cytokines. Breg cells can produce IL-10 to inhibit effector T cell function and enhance Treg cell function. Furthermore, IL-35 secretion by Breg cells can inhibit the proliferation of naive effector T cells. In contrast, Beff cells produce proinflammatory cytokines, including interleukin (IL)-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, to promote effector and memory CD4+ T cell responses. At the same time, these cytokines might play a non-cytolytic antiviral role for infected hepatocytes via inducing cccDNA decay or reducing HBV transcription. In addition, IL-6 secretion by Beff cells can also inhibit HBV entry by regulating the expression of an HBV-specific receptor, known as NTCP. NTCP: Na(+)/taurocholate co-transporting polypeptide; Breg cells: regulatory B cells; Beff cells: effector B cells.