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

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.712105

DOI=10.3389/fcimb.2021.712105

ISSN=2235-2988

ABSTRACT=<p>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-<italic>γ</italic>, 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, <italic>p</italic> =0.003 and r = −0.384, <italic>p</italic> = 0.040). Treg correlated with CTL and Th1 at the lobular area (r = 0.784, <italic>p</italic> &lt; 0.0001; r = 0.436, <italic>p</italic> = 0.013). Th17 correlated with hepatic IL-8 (r = 0.52, <italic>p</italic> &lt; 0.05), and both were higher in advanced fibrosis cases (Th17 <italic>p</italic> = 0.0312, IL-8 <italic>p</italic> = 0.009). Hepatic cytokines were higher in severe hepatitis cases (IL-1β <italic>p</italic> = 0.026, IL-23 <italic>p</italic> = 0.031, IL-8 <italic>p</italic> = 0.002, TGF-β, <italic>p</italic>= 0.037). Peripheral NK (<italic>p</italic> = 0.008) and NK <italic>dim</italic> (<italic>p</italic> = 0.018) were diminished, while NK <italic>bright</italic> (<italic>p</italic> = 0.025) was elevated in patients <italic>vs.</italic> donors. Naïve Th (<italic>p</italic> = 0.011) and CTL (<italic>p</italic> = 0.0007) were decreased, while activated Th (<italic>p</italic> = 0.0007) and CTL (<italic>p</italic> = 0.0003) were increased. IFN-<italic>γ</italic> production and degranulation activity in NK and CTL were normal. Peripheral cytokines showed an altered profile <italic>vs.</italic> donors, particularly elevated IL-6 (<italic>p</italic> = 0.008) and TGF-β (<italic>p</italic> = 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.</p>