ANOMALOUS EXPRESSION OF COSTIMULATORY MOLECULES B7-1, B7-2 AND CD28 IN PRIMARY BILIARY-CIRRHOSIS

Background: T lymphocytes require two important signals for efficient activation: 1) recognition of antigens bound to self major histocompat ibility complex antigens, and 2) simultaneous stimulation via so-calle d costimulatory molecules. Interaction of the costimulatory B7 molecul es on antigen presenting cells with CD28 on T lymphocytes appears to b e particularly important, as it modifies secretion of cytokines, espec ially interleukin 2. In primary biliary cirrhosis biliary epithelial c ells aberrantly express major histocompatibility complex class II anti gens and may function as antigen presenting cells. Methods: We studied expression of HLA-DR, B7-1, B7-2 and CD28 on cryostat liver sections in 16 patients with primary biliary cirrhosis, three patients each wit h autoimmune hepatitis and primary sclerosing cholangitis and nine pat ients with chronic viral hepatitis (five hepatitis B, four hepatitis C ) using mouse monoclonal antibodies in an indirect immunoperoxidase te chnique. Results: In advanced primary biliary cirrhosis, HLA-DR was fo und on 57% of bile ducts, B7-2 on 5% of bile ducts, and B7-1 could not be detected on any bile duct. Neither B7-1 nor B7-2 was seen on bile ducts in the four patients with early primary biliary cirrhosis. HLA-D R+ bile ducts also lacked expression of B7 molecules in autoimmune hep atitis. In contrast, HLA-DR, B7-1 and B7-2 were expressed simultaneous ly on professional antigen presenting cells such as macrophages in epi theloid granulomas. Conclusion: HLA-DR+ biliary epithelial cells in pr imary biliary cirrhosis insufficiently co-express B7-1 or B7-2 molecul es. Therefore, they must either use different costimulatory molecules, or otherwise are deficient in lymphocyte activation. Since recognitio n of antigen in the absence of B7-CD28 interaction may lead to anergy of lymphocytes, this might contribute to the impaired cytokine secreti on found in primary biliary cirrhosis.