Immunology of Acute and Chronic Viral Hepatitis

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

Chronic HBV infection progresses through distinct phases often with flares in disease severity. Flares cannot be predicted, and their pathogenesis is unknown. We continued our studies on immune responses that contribute to flares of increased inflammation in chronic HBV infection. Because the prevalence of such disease flares is increased in the third trimester of pregnancy and postpartum, we prospectively study immune responses of HBV-infected patients and uninfected controls during pregnancy and postpartum using cryopreserved peripheral blood mononuclear cells. The patients were clinically followed Dr. Daryl Lau, Harvard Medical School, and bio-samples were sent to NIH. We found that myeloid cells of patients who did not develop flares had a significantly reduced expression of inflammatory genes and pathways compared to monocytes of HBV patients who later-on developed flares and compared to myeloid cells of healthy pregnant women without HBV infection. We devised functional immune assays to assess myeloid cell responses to inflammatory stimuli. These assays are now being used to monitor inter-individual variability of myeloid cell responses during pregnancy and postpartum in this patient population and in uninfected controls. Additionally, we established scRNA sequencing techniques to characterize intrahepatic immune responses in serial liver biopsies and fine needle aspirates from patients treated in the Liver Diseases Branch, NIDDK. Importantly, scRNA seq techniques also allow us to assess changes in the transcriptome of myeloid cells, a population of diverse innate immune cells that we had shown to be significantly increased in size and activated by complex, natural microbiota (Immunity 2025, PMID 40730165) and that is not assessed in standard immunological studies on viral hepatitis. We started using these techniques in a translational study (protocol IRB001606) to investigate whether siRNA-mediated suppression of HBV surface antigen production enhances innate and adaptive immune responses to HBV and results in functional cure. Functional cure is defined as the lasting absence of HBV DNA and hepatitis B surface antigen in the circulation after end of treatment. This study has enrolled the first patient, whose immune response we are studying prospectively both in the liver (biopsies and fine needle aspirates) and blood.