title: The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection.
abstract: Cytotoxic T lymphocytes (CTL) and Kupffer cells play an important role in the immune control of hepatitis B virus (HBV), but may also induce liver injury during infection. We investigated the intrahepatic immune response in liver biopsies of chronic HBV patients in relation to inflammatory liver injury and viral control. Forty-seven liver biopsies from patients with chronic HBV with varying degrees of inflammation (ALT values) were selected. Acute hepatitis and normal liver specimens served as controls. Immune effector cells, cytotoxic effector molecules and cytokine producing cells were quantified after immunohistochemical staining in lobular and portal areas of the biopsies. The intralobular number of CD8+ T-lymphocytes was significantly decreased in biopsies of patients with high ALT (r = -0.54; P < 0.001). Higher ALT-values were correlated with increased numbers of granzyme+ cells in portal areas (r = 0.65; P < 0.001) and higher numbers of intralobular Fas-L+ cells (r = 0.32; P = 0.05). Fas-L was expressed on Kupffer and lymphoid cells. More intralobular CD8+ T-lymphocytes were found in HBeAg- than in HBeAg+ patients (P = 0.002). But IFN-gamma and TNF-alpha producing cells were observed sporadically in chronic HBV patients. Hence, in chronic HBV infection, low viral replication and HBeAg negativity is related to increased presence of intralobular CD8+ T-lymphocytes. Persistence of the virus may be caused by the absence of cells producing anti-viral cytokines in the liver. Inflammatory liver injury during chronic HBV infection is probably not the result of increased numbers of infiltrating CD8+ T-lymphocytes, but of Fas-L expression by Kupffer cells and increased cytolytic activity of cells in portal areas.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, the Netherlands.
authors.forename: T J
authors.initials: TJ
authors.lastname: Tang
authors.forename: J
authors.initials: J
authors.lastname: Kwekkeboom
authors.forename: J D
authors.initials: JD
authors.lastname: Laman
authors.forename: H G M
authors.initials: HG
authors.lastname: Niesters
authors.forename: P E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: R A
authors.initials: RA
authors.lastname: de Man
authors.forename: S W
authors.initials: SW
authors.lastname: Schalm
authors.forename: H L A
authors.initials: HL
authors.lastname: Janssen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D053222:Fas Ligand Protein; D005260:Female; D053804:Granzymes; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016898:Interferon-alpha / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D018655:Lymphocyte Count; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D012697:Serine Endopeptidases / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases