Cytokines and Chemokines in HBV Infection

Abstract

Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatic inflammation and damage. The pathogenesis of chronic hepatitis B (CHB) infection is predominantly mediated by persistent intrahepatic immunopathology. With the characterization of unique anatomical and immunological structure, the liver is also deemed an immunological organ, which gives rise to massive cytokines and chemokines under pathogenesis conditions, having significant implications for the progression of HBV infection. The intrahepatic innate immune system is responsible for the formidable source of cytokines and chemokines, with the latter also derived from hepatic parenchymal cells. In addition, systemic cytokines and chemokines are disturbed along with the disease course. Since HBV is a stealth virus, persistent exposure to HBV-related antigens confers to immune exhaustion, whereby regulatory cells are recruited by intrahepatic chemokines and cytokines, including interleukin-10 and transforming growth factor β, are involved in such series of causal events. Although the considerable value of two types of available approved treatment, interferons and nucleos(t)ide analogues, effectively suppress HBV replication, neither of them is sufficient for optimal restoration of the immunological attrition state to win the battle of the functional or virological cure of CHB infection. Notably, cytokines and chemokines play a crucial role in regulating the immune response. They exert effects by directly acting on HBV or indirectly manipulating target immune cells. As such, specific cytokines and chemokines, with a potential possibility to serve as novel immunological interventions, combined with those that target the virus itself, seem to be promising prospects in curative CHB infection. Here, we systematically review the recent literature that elucidates cytokine and chemokine-mediated pathogenesis and immune exhaustion of HBV infection and their dynamics triggered by current mainstream anti-HBV therapy. The predictive value of disease progression or control and the immunotherapies target of specific major cytokines and chemokines in CHB infection will also be delineated.

Immune Checkpoint Molecules Expressed on CD4+ T Cell Subsets in Chronic Asymptomatic Hepatitis B Virus Carriers With Hepatitis B e Antigen-Negative

“…These findings implied that chronic HBV infection resulted in the host’s immune disorder and dysregulation by upregulating immune checkpoint molecules, including TIM-3, PD-1, CTLA-4, and LAG-3 on T cells, that induced T-cell dysfunction in chronic HBV infection. In addition, our results showed that serum cytokines (IL-2, IL-4, and TNF-a) had a low trend in chronic ASCs with HBeAg-negative in comparison with HC, which were partially consistent with previous reports ( Ayada et al, 2006 ; Wang X. et al, 2018 ; Zhong et al, 2021 ). These cytokines play a critical role in regulating CD4/CD8 + T cell proliferation and differentiation and the production of various specific antibodies to control persistent HBV infection ( Buschow and Jansen, 2021 ; Mak et al, 2021 ; Zhong et al, 2021 ).…”

“…In addition, our results showed that serum cytokines (IL-2, IL-4, and TNF-a) had a low trend in chronic ASCs with HBeAg-negative in comparison with HC, which were partially consistent with previous reports ( Ayada et al, 2006 ; Wang X. et al, 2018 ; Zhong et al, 2021 ). These cytokines play a critical role in regulating CD4/CD8 + T cell proliferation and differentiation and the production of various specific antibodies to control persistent HBV infection ( Buschow and Jansen, 2021 ; Mak et al, 2021 ; Zhong et al, 2021 ).…”

Efficient cellular and humoral immune response and production of virus-neutralizing antibodies by the Hepatitis B Virus S/preS116-42 antigen

“…Similarly, IL-6 inhibits HBV transcription by epigenetic mechanisms, in addition to performing a broad range of pro-and anti-inflammatory signaling (36). This pro-inflammatory cytokine pattern is similar to that resulted after the viral infection or TLR-9 stimulation, suggesting a crosstalk between that innate and adaptive immunity influencing the antigen specific immune response (34,67). Clearly, further research involving more relevant animal models is needed to understand the true benefit of a particular Tcell activation pattern.…”

“…Clearly, further research involving more relevant animal models is needed to understand the true benefit of a particular Tcell activation pattern. This will ultimately depend on the fine balance between the capacity of the complex cytokine-mediated pathways to boost anti-HBV immunity on one hand, and to potentially cause liver inflammation, on the other (34). An important finding emerging from this study is the equivalence of the S and S/preS1 antigens produced in mammalian cells in terms of activating an efficient WT HBVneutralizing humoral immune response and the evident superiority of the latter immunogen to prevent infection with the G145R vaccine-escape mutant.…”

“…The clustered heatmap resulting from this analysis indicates a broad spectrum of HBV-reactive T cells generated by immunization with the S and S/preS1 antigens (Figure 6). The complexity of this immune response is illustrated by the presence of pro-(TNF-a, IL-1b, IL-6, IL-17A) and anti-inflammatory cytokines (IL-10) (34), some of them with known antiviral activity against HBV (IL-1b, IL-6, IL-17A) (35)(36)(37). Importantly, both immunogens induced secretion of IFN-g, the well-accepted marker of Th cell activation, above the levels found in controls; however, this was not the predominant cytokine (Figure 6).…”