Immunology of Acute and Chronic Viral Hepatitis

National Institute Of Diabetes And Digestive And Kidney Diseases

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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. Seven (58%) treatment-nave and 2 (33%) NUC-treated patients developed perinatal hepatic flares. While plasma levels of soluble CD163, inflammatory cytokines, and chemokines increased during hepatic flares, IL-22 and IFN-gamma levels increased prior to a postpartum hepatic flare in one case. Plasma levels of IL-27, a cytokine produced by the trophoblast, increased in the 3rd trimester even in women with normal ALT levels. The fecal microbiota of hepatitis B virus-infected patients with and without NUC therapy had a lower a-diversity (inverse Simpson index) than those of uninfected controls. 16S rRNA amplicon analysis and principal component analysis revealed patient-specific clustering of the microbiota. To identify predictive factors for postpartum hepatic flares, we compared 16S rRNA DNA data from patients with and without a postpartum hepatic flare (four patients per group). The gut microbiota of those with a hepatic flare was significantly different from those without an hepatic flare and the difference was maintained at all study time points. In conclusion, the current results show that a postpartum ALT increase was preceded by an IL-27, and/or IL-22 and IFN-g increase during pregnancy. The composition of the fecal microbiota was found to be patient- rather than time-point-dependent and differed between patients with and without postpartum liver disease flares. Further analysis of the innate and adaptive immune cell population throughout the course of the study is currently in progress. While studying the immune response of the above-described cohort, we were able to follow a case of recurrent intrahepatic cholestasis of pregnancy. Intrahepatic cholestasis is one of the most common liver diseases during the second and third trimesters of pregnancy, but its pathogenesis remains unclear. Intrahepatic cholestasis of pregnancy is associated with elevations of maternal bile acids, serum aminotransferases, and adverse fetal outcomes. Besides direct cytotoxic liver injury by bile acids, it has been suggested that bile acid-induced oxidative studied innate immune responses in a rare patient who presented with recurrent intrahepatic cholestasis. The observed case was atypical for her serum aminotransferases increased postpartum despite normalization of bile acids in two subsequent pregnancies. We demonstrated that the extended elevation of serum aminotransferases after normalization of bile acid levels coincides with an extended increase of the chemokine CXCL10 and inflammatory cytokines. We hypothesize that the elevated bile acid levels lead to hepatic recruitment of immune cells which express the CXCR3 receptors for CXCL10. The subsequent immune cell activation with release of IFN-g may maintain the inflammatory response and contribute to the prolonged ALT elevation even after the bile acid levels returned to normal.