Detection and Significance of Cytotoxic Cell Subsets in Biopsies of HCV-Infected Human Livers

Abstract

Chronic viral hepatitis C still remains the clinical challenge. Attempts of the immune system to cope with this infection are unsatisfactory. There is a conviction that the main site of interaction between virus (Hepatitis C virus, HCV) and immune system is in situ, i.e., in liver. Natural killer (NK) cells appeared relevant in the acute hepatitis. Less is known about the immune response in the chronic HCV infection. The aim of this study was to evaluate the prevalence of various cytotoxic cell subsets in chronic HCV+ liver tissue and to seek links between them and laboratory data of patients. Sections from paraffin blocks of liver biopsy tissues of HCV+ untreated patients were subjected to the reaction with antibodies vs. cytotoxic cell subsets and immunohistochemistry. Positive cells were searched in cellular infiltrates in portal areas and in liver parenchyma. They were classified on the “Yes” or “No” basis. Majority of liver biopsies exhibited cellular infiltrates in portal spaces and as single cells in liver parenchyma. Infiltrates consisted of CD8+ T cells, CD56+ NK ones, including CD158i+ and CD158b+. The latter were rarely seen. There were also granzyme B+ cells. The most abundant were NKG2D+ cells, much more common than NK CD56+ ones. It implied that NKG2D was also expressed on T cells. Prevalence of NKG2D+ cells correlated with high activity of liver enzymes such as alanine aminotransferase, aspartate aminotransferase and a greater histological severity of liver injury. NKG2D+ cells form the bulk of cells infiltrating HCV-infected human liver. Correlation of NKG2D+ cells with some laboratory parameters of patients suggests their role in hepatitis C pathogenesis.

Genetic (KIR, HLA-C) and Some Clinical Parameters Influencing the Level of Liver Enzymes and Early Virologic Response in Patients with Chronic Hepatitis C

“…KIR2DS4 gene, without determining full-length versus deleted variants, was found protective against HCV infection, elevated ALT levels and cirrhosis in Argentinian Caucasians (Paladino et al 2007 ) and in exposed intravenous drug users of Puerto Rican descent (Zúñiga et al 2009 ). We have also described recently a correlation between ALT and AST levels before therapy and expression of another activating NK cell receptor, NKG2D, in livers of HCV-infected individuals (Mozer-Lisewska et al 2014 ). In that study, we found a higher abundance of NKG2D + cells than that of CD56 + cells in liver infiltrates, which suggests that other cells, presumably T cells, expressed NKG2D in addition to NK cells.…”

Adaptive Immune Responses, Immune Escape and Immune-Mediated Pathogenesis during HDV Infection

“…The authors, therefore, concluded that there is a general antigen-nonspecific activation of the resident memory CD8+ T cells contributing to disease stage and inflammation [160]. The increased expression of NKG2D on liver-infiltrating CD8+ T cells was also observed in chronic HBV and HCV infection, and likewise correlated in HCV infection with a higher activity of liver enzymes and a greater histological severity of liver injury [173,174]. Whereas NKG2D acts as a direct activator on NK cells, triggering cytotoxicity and cytokine secretion [175][176][177], Kennedy et al demonstrated that it is a co-stimulatory molecule acting in synergy with the TCR on HBV-specific CD8+ T cells, similar to other viral infections [174,178].…”