Immunology of Acute and Chronic Viral Hepatitis

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

Chronic HBV infection progresses through distinct phases often with flares in disease severity. Flares cannot be predicted, and their pathogenesis is unknown. Pregnancy represents an excellent model to study the role of immune responses in disease flares because flares occur predominantly in the third trimester of pregnancy and after delivery. Supported by an NIH Bench-to-Bedside Award, we are studying innate and adaptive immune responses and the gut microbiome prospectively in HBV-infected patients and uninfected controls during pregnancy and postpartum. The patients are clinically followed by my collaborator Dr. Daryl Lau, Harvard Medical School, and bio-samples are sent to NIH. To date, we have prospectively collected blood and stool samples from 18 HBV patients and 4 uninfected patients, and 19/22 patients reached the study end point. We found that flares in ALT activity correlate with increased levels of HBV DNA, inflammatory cytokines and NK cell activation. Microbiome analysis is ongoing and single cell analysis of innate and adaptive immune responses will be performed. The results will provide insights into the immunopathogenesis of HBV infection and may identify biomarkers that predict flares. Chronic HBV/HDV coinfection accelerates liver disease progression to fibrosis, cirrhosis and hepatocellular carcinoma. To gain insight into the pathogenesis of this disease we studied innate and adaptive immune responses in blood and liver of 24 HDV-infected patients and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage. We found that the 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. 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 (r=1.0). 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 and by in vitro demonstration of cytokine-induced NKDG2D-dependent cytotoxicity. The results suggest that antigen-nonspecific activation of liver-resident CD8+ T cells contribute to inflammation and disease stage in HDV infection.