Chronically Inflamed Livers Up-Regulate Expression of Inhibitory B7 Family Members

Hepatitis B virus, hepatitis C virus, autoimmune hepatitis, and nonalcoholic fatty liver disease can induce chronic liver disease. The Programmed Death-1 (PD-1) inhibitory pathway assists in T cell response regulation during acute and chronic inflammation and participates in the progression of inflammatory liver disease. To examine whether PD-1 and its ligands, B7-H1 and B7-DC, are modulated during chronic necroinflammatory liver disease, we investigated expression profiles in normal patients and patients with the aforementioned conditions. Relative to liver biopsies from normal individuals, those from patients with chronic necroinflammatory liver diseases (hepatitis B virus, hepatitis C virus, and autoimmune hepatitis) contain increased numbers of PD-1-expressing lymphocytes. Kupffer cells, liver sinusoidal. endothelial cells, and leukocytes express PD-1 ligands. We also detect PD-1 ligands on hepatocytes within biopsies and on isolated cells. All forms of chronic necroinflammatory liver disease examined correlate with increased B7-H1 and B7-DC expression on Kupffer cells, liver sinusoidal epithelial cells, and leukocytes. The degree of necroinflammation correlates with expression levels of PD-1 family members. Conclusion: These results demonstrate that expression of PD-1/PD-1 ligands links more directly with the degree of inflammation than with the underlying etiology of liver damage. The PD-1 pathway may assist the liver in protecting itself from immune-mediated destruction. (HEPATOLOGY 2009;50: 1625-1637.)