Immunology of Acute and Chronic Viral Hepatitis

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

The hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5-10 years. There is no curative treatment and the mechanisms underlying the accelerated liver disease progression are unknown. While immune responses have recently been characterized in the blood of HDV-infected patients, immune responses have not been studied in the liver, the site of infection. Here, we hypothesized that the rapid disease progression results from generalized activation of both the innate and adaptive immune system, defined as bystander activation. Here, we studied innate and adaptive immune responses in blood and liver samples from HDV-infected patients and uninfected subjects by multiparameter flow cytometry, in correlation with disease severity and stage. We found that two main intrahepatic innate immune-cell populations, MAIT cells and NK cells, were reduced in the livers of HDV-infected patients compared to those of uninfected controls but were more frequently activated in the liver compared to the blood. For analysis of HDV-specific CD8 T cells we mapped CD8 T cell epitopes and used MHC-epitope multimers and to characterize HDV-specific CD8 T cells ex vivo in untreated patients. Most intrahepatic CD8+ T cells were memory cells or terminal effector memory cells, and the majority of activated and degranulating (CD107a+) HDV-specific and total CD8+ T cells were liver-resident (CD69+CXCR6+). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8+ T-cell cluster with expression of innate-like NKp30 and NKG2D receptors. The size of this population correlated with liver enzyme activity. NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8+ T-cell population suggesting global bystander activation. This was supported by the correlations between NKG2D expression and degranulation of intrahepatic CD8+ T cells and between frequency of degranulating CD8+ T cells and liver enzyme activity, and APRI score. Cytokine-induced bystander activation of CD8 T cells resulted in NKG2D-medated lysis of hepatoma cells as demonstrated by in vitro experiments. In conclusion, HDV infection is associated with broad activation of the innate and adaptive immune system. Bystander immune cell activation likely contributes to liver disease progression.