Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma

Abstract

Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.

Keywords: adaptive immunity; hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; innate immunity.

Figure 1

Structure of hepatitis B and hepatitis C viruses. (a) Genomic structure of HBV, left panel: The hepatitis B viral envelope encases an icosahedral nucleocapsid, which involves a 3.2-kilobase relaxed circular DNA (rcDNA) genome consisting of a full-length negative strand and partial positive strand. This partially double-stranded HBV genome encodes four open reading frames (ORFs), namely known as P (polymerase), S (surface), C (core), and X (HBx protein) [3]. Genes encoded for HBV genetic materials are PreS1/PreS2/S, which encodes HBsAg; P, which encodes translating polymerase, PreC/C encoding core protein; and X, which encodes HBx protein. Translation of S gene gives large, medium, and small HBsAg, while capsid protein is translated from C gene. HBeAg is translated from the pre-C gene. (b) Genomic structure of HCV, right panel: HCV is a 9.6 kb single-stranded positive RNA with one ORF flanked by 2 untranslated regions. The N-terminal ORF encodes HCV structural glycoproteins (core, E1 and E2), whereas the rest of the viral ORF encodes other non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) [27].

Figure 2

Immune response to acute HBV infection. Various viral antigens activate different adaptive immune cell subsets, initiating the host response to viral entry. PAMPs released from infected hepatocytes activate macrophages/Kupffer cells, NK, and NKT cells to secrete pro-inflammatory and anti-viral cytokines that decrease viral replication while promoting apoptosis in infected hepatocytes. PAMPs also activate antigen-presenting cells to initiate the adaptive immune response and successful viral clearance. Abbreviation: HBV; hepatitis B virus, IL6; interleukin 6, IL8; interleukin 8, IL1β; Interleukin 1, β, iNOS; inducible nitric oxide synthase, TNFα; tumor necrosis factor α, PAMPs; pathogen-associated molecular pattern, IFN; interferons; TRAIL; TNF-related apoptosis-inducing ligand. Figure created with BioRender.com.

Figure 3

Different immune subsets in chronic HBV infection. TLR signaling molecules are impaired in macrophages exposed to different HBV antigens, leading to the inactivation of dendritic cells and the recruitment of the immunosuppressive Treg cells to the diseased liver microenvironment. High and low viraemia activate low cytolytic HBV-specific CD8⁺T-cells and exhausted CD8⁺T cells, respectively, leading to viral persistence. HBcAg induces the accumulation of the immunosuppressive CD4⁺T-cells that fail to activate the CD8⁺T-cell response. Abbreviations: TLR: Toll-Like Receptor; IFNα: Interferon α; IRF: Interferon Regulatory Factor 3; PD1: Programmed Death-1; PDL1: Programmed Death Ligand 1; IL: Interleukin; JMJD6: Jumonji Domain Containing 6; CDKN3: Cyclin-Dependent Kinase Inhibitor 3; SUMO1: Small Ubiquitin-Like Modifier 1; AREG: Amphiregulin; MyD88: Myeloid Differentiation Primary Response 88. Figure created with BioRender.com.

Figure 4

Immune response to the acute HCV phase. Infected hepatocytes release PAMPs, viral antigens, or interferons to activate various innate immune responses. While PAMPs activate interferon signaling in macrophages and dendritic cells, HCV E2 protein activates NK cells to release more IFNs that contribute to the reduced viral replications. The strength of the adaptive immune response to the initial phase of HCV infection detects the infection outcome; a strong intrahepatic T-cell response was associated with viral eradication, while the absence of this adaptive response favors viral persistence. The 2nd and 3rd HCV infections were associated with strong viral eradication and the production of memory T-cell phenotype. Abbreviations: IFN, interferon; TLR, Toll-Like Receptor; RIG1, RNA helicases retinoic acid-inducible gene-1; MDA5, melanoma differentiation antigen 5; IL21, Interleukin 21. Figure created with BioRender.com.

Figure 5

Chronic HCV infection and activation of different immune subsets. Macrophages engulf HCV, releasing CCL5 that activates quiescent hepatic stellate cells to induce liver fibrosis. Macrophages also release the proinflammatory IL6 and IL1β cytokines to the diseased liver microenvironment. An increase in IL10 also diminishes the NK-mediated release of IFNs, leading to viral persistence. HCV-specific CD8+T-cells also acquire an exhausted phenotype due to the abundance of different regulatory T-cell phenotypes and the upregulation of PDL1 on the surface of macrophages and dendritic cells. Abbreviations: SOCS-1, Suppressor Of Cytokine Signaling 1; NCR, Natural Cytotoxicity Triggering Receptor 1; C-C Motif Chemokine Ligand 5; TGFβ, Transforming Growth Factor Beta 1; CTLA4, Cytotoxic T-Lymphocyte Associated Protein 4. Figure created with BioRender.com.

Figure 6

The interplay between different immune cells in HBV-HCC. NK cells in chronic HBV infection and HBV-HCC express different inhibitory receptors and secrete many fibrogenic and proinflammatory cytokines that participate in disease progression. While NKT cells stimulate hepatic stellate cell activation in chronic HBV patients, macrophages also induce fibrosis via interaction with CD8+TRM. HBV-specific CD8+T and CD4+T-cells lose their cytolytic activity and eradicate neither HBV infection nor the HBV-HCC tumor cells. Moreover, Tregs induce their immunotolerant role in both chronic infection and HCC, leading to disease progression and aggressiveness. Figure created with BioRender.com.