R. Volpes

Hepatic expression of type A and type B receptors for tumor necrosis factor

We have examined the in-situ distribution of type A and type B receptors for tumor necrosis factor (TNF) in normal and diseased human liver biopsy specimens. In normal liver tissue, no or very small amounts of TNF receptors were found. In acute and chronic inflammatory liver diseases, a strong up-regulation of the expression of both TNF receptors was found on hepatocytes, bile duct epithelium, sinusoidal lining cells and mononuclear inflammatory cells. With immunoelectronmicroscopy, all these cells showed cytoplasmic, in addition to membranous staining, suggesting active synthesis of the receptor or, alternatively, internalization of the receptor and its ligand. This up-regulated expression of both type A and type B receptors for TNF was similar in acute and chronic active hepatitis, and was not related to the etiology of the liver disease, nor restricted to areas of liver inflammation. Our results indicate that hepatocytes, sinusoidal endothelial cells, bile duct epithelial cells and mononuclear inflammatory cells, by displaying receptors for TNFs, represent target cells for both these cytokines. Up-regulated expression of type A and type B receptors for TNFs endows these cells with augmented responsiveness for the pleiomorphic biological activities of these cytokines during liver injury.

LAM-1/Leu 8 antigen is expressed on portal, but not on lobular intrahepatic mononuclear cells in inflammatory liver disease.

The expression of the selectin receptor LAM‐1/Lcu 8 was analysed in normal and in inflamed liver tissue, and its expression on mononuclear inflammatory cells was correlated with their topographical distribution in various compartments of the inflamed liver, in order to obtain new insights on possible molecular mechanisms involved in the traffic of mononuclear inflammatory cells throughout the diseased hepatic parenchyma. In normal liver tissue, few scattered mononuclear cells in portal and lobular parenchyma corresponded to both CD4+ and CD8+, as well as to CD45RA+ (2H4+) naive and CD45RO+ (UCHL1 +) memory T cells, and were LAM‐1 /Leu 8+. In acute and chronic inflamed liver biopsies. CD45RO+ (UCHL1 +)CD4+ and CD8+ memory T cells largely predominated in both portal and lobular parenchyma. The expression of LAM‐ 1/Leu 8 antigen on these memory T cells varied according to their localization in the liver parenchyma, and it was not correlated with specific aetiological causes. In acute hepatitis, the vast majority of T lymphocytes were LAM‐1/Leu 8. In chronic active hepatitis, memory T cells in portal tracts expressed LAM‐1 /Leu 8. whereas virtually all intralobular T cells accumulating in areas of periportal and intralobular inflammation were LAM‐1/ Leu 8. In chronic persistent hepatitis, the LAM‐1/Leu 8+ T cells largely predominated among the numerous mononuclear inflammatory cells within enlarged portal tracts, whereas LAM‐1/Leu 8 T cells were restricted to areas of intralobular ‘spotty’ inflammation. Therefore, two phenotypical populations can be recognized among the memory T cells in inflamed liver tissue, according to their topographical localization: LAM‐1/Leu 8+ Tcells predominating in portal tracts, and LAM‐1/Leu 8 T cells predominating in the lobular parenchyma. These data show that during their migration through the inflamed liver parenchyma, memory T lymphocytes undergo phenotyical changes (LAM‐1/Leu 8 shedding) according to their localization in different liver compartments (portal tracts vs. lobular parenchyma), suggesting multiple cellular and molecular mechanisms involved in the regulation of the leucocyte traffic through inflamed liver tissue.

Homing of T-lymphocytes in acute and chronic HBV positive inflammatory liver disease

The expression of immune adhesion molecules governing cell-cell and cell-matrix interactions allows an optimal migration and accumulation of lymphocytes in acute and chronic inflammatory liver diseases.