Pathogenesis of viral hepatitis based on intrahepatic immune response to hepatitis virus

研究了小鼠肌肉DNA免疫和表达乙型肝炎病毒基因组（Ad-HBV）的重组腺病毒感染后，细胞毒性T淋巴细胞（CTL）对乙型肝炎表面抗原（HBsAg）的反应分布和动态。DNA免疫后，HBsAg特异性ctl优先在脾脏积聚，但在Ad-HBV感染后主要在肝内积聚。dna引物小鼠对Ad-HBV的继发性CTL反应的特征是脾脏中效应CTL的快速消耗，它们在肝脏中扩张，在那里它们引起肝炎，分泌干扰素γ (IFNγ)，并抑制HBV基因表达。与肝内IFNγ表达一起，CXCL9和CXCL10 mrna在肝脏中被强烈诱导。抑制HBsAg的合成伴随着肝内产生ifn - γ的ctl的消失及其在脾脏中的重新积聚。这些数据为慢性HBV感染期间外周HBV特异性CTL的缺乏和功能缺陷提供了可能的解释，并且如果不存在中和抗体，则先前存在的CTL反应可能会使感染的严重程度恶化。

The distribution and dynamics of the cytotoxic T lymphocyte (CTL) response to hepatitis B surface antigen (HBsAg) were studied in mice after intramuscular DNA immunization and after hepatic infection by a recombinant adenovirus that expresses the hepatitis B virus genome (Ad-HBV). CTLs specific for HBsAg accumulate preferentially in the spleen after DNA immunization but are primarily intrahepatic after Ad-HBV infection. The secondary CTL response to Ad-HBV in DNA-primed mice is characterized by rapid depletion of effector CTLs from the spleen, and their expansion in the liver where they cause hepatitis, secrete interferon gamma (IFNγ), and inhibit HBV gene expression. Together with intrahepatic IFNγ expression, CXCL9 and CXCL10 mRNAs were strongly induced in the liver. Suppression of HBsAg synthesis is accompanied by disappearance of intrahepatic IFNγ-producing CTLs and their reaccumulation in the spleen. The data suggest a possible explanation for the paucity and functional deficiency of HBV-specific CTLs in the periphery during chronic HBV infection, and that the severity of infection can be worsened by a preexisting CTL response if neutralizing antibody is not also present.