Chronic Hepatitis C Pathogenesis: Immune Response in the Liver Microenvironment and Peripheral Compartment.

Daniela Alejandra Rios,Cecilia Giadans,María Victoria Preciado,María Soledad Caldirola,Paola Cecilia Casciato,Elena Noemí De Matteo,Pamela Valva,María Isabel Gaillard,Beatriz Ameigeiras

doi:10.3389/fcimb.2021.712105

Abstract

Chronic hepatitis C (CHC) pathogenic mechanisms as well as the participation of the immune response in the generation of liver damage are still a topic of interest. Here, we evaluated immune cell populations and cytokines in the liver and peripheral blood (PB) to elucidate their role in CHC pathogenesis. B, CTL, Th, Treg, Th1, Th17, and NK cell localization and frequency were evaluated on liver biopsies by immunohistochemistry, while frequency, differentiation, and functional status on PB were evaluated by flow cytometry. TNF-α, IL-23, IFN-γ, IL-1β, IL-6, IL-8, IL-17A, IL-21, IL-10, and TGF-β expression levels were quantified in fresh liver biopsy by RT-qPCR and in plasma by CBA/ELISA. Liver CTL and Th1 at the lobular area inversely correlated with viral load (r = −0.469, p =0.003 and r = −0.384, p = 0.040). Treg correlated with CTL and Th1 at the lobular area (r = 0.784, p < 0.0001; r = 0.436, p = 0.013). Th17 correlated with hepatic IL-8 (r = 0.52, p < 0.05), and both were higher in advanced fibrosis cases (Th17 p = 0.0312, IL-8 p = 0.009). Hepatic cytokines were higher in severe hepatitis cases (IL-1β p = 0.026, IL-23 p = 0.031, IL-8 p = 0.002, TGF-β, p= 0.037). Peripheral NK (p = 0.008) and NK dim (p = 0.018) were diminished, while NK bright (p = 0.025) was elevated in patients vs. donors. Naïve Th (p = 0.011) and CTL (p = 0.0007) were decreased, while activated Th (p = 0.0007) and CTL (p = 0.0003) were increased. IFN-γ production and degranulation activity in NK and CTL were normal. Peripheral cytokines showed an altered profile vs. donors, particularly elevated IL-6 (p = 0.008) and TGF-β (p = 0.041). Total hepatic CTLs favored damage. Treg could not prevent fibrogenesis triggered by Th17 and IL-8. Peripheral T-lymphocyte differentiation stage shift, elevated cytokine levels and NK-cell count decrease would contribute to global disease.

Highlights

IntroductionChronic hepatitis C (CHC) still represents a major global health problem affecting approximately 71 million people worldwide (Polaris Observatory hepatitis C virus (HCV) Collaborators, 2017); the real burden of HCV infection displays great uncertainty since most infected people remain undiagnosed and untreated
Chronic hepatitis C (CHC) is a progressive disease that may result in cirrhosis and/or hepatocellular carcinoma; liver failure because of hepatitis C virus (HCV) infection is one of the most common reasons for liver transplantation (Manns et al, 2017).CHC still represents a major global health problem affecting approximately 71 million people worldwide (Polaris Observatory HCV Collaborators, 2017); the real burden of HCV infection displays great uncertainty since most infected people remain undiagnosed and untreated
The immune response has a dual role during the course of HCV infection, so in this manuscript we intended to evaluate the potential interplay between the virus and the liver immune microenvironment in CHC

Summary

Introduction

CHC still represents a major global health problem affecting approximately 71 million people worldwide (Polaris Observatory HCV Collaborators, 2017); the real burden of HCV infection displays great uncertainty since most infected people remain undiagnosed and untreated In this context one of the major current challenges is to carry out screening programs to assess CHC in the context of an asymptomatic infection (Hollande et al, 2020). Given that there is no protective vaccine approved, the highly effective direct-acting antiviral agents (DAAs) are of great importance since they reach a dramatically high-sustained virological response (SVR) rate They cannot fully eradicate hepatocellular carcinoma risk, especially in HCV-cured patients with advanced liver disease, suggesting an accumulation of irreversible damages to the liver during long-term HCV infection (Reig et al, 2017; Goto et al, 2020; Massoud, 2020; Sangiovanni et al, 2020). Knowledge of the CHC pathogenic mechanisms as well as of the participation of the immune response in the generation of liver damage (Tang et al, 2016; Manns et al, 2017) is still a topic of interest

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