Anomalous expression of costimulatory molecules B7-1, B7-2 and CD28 in primary biliary cirrhosis

Abstract

Background: T lymphocytes require two important signals for efficient activation: 1) recognition of antigens bound to self major histocompatibility complex antigens, and 2) simultaneous stimulation via so-called costimulatory molecules. Interaction of the costimulatory B7 molecules on antigen presenting cells with CD28 on T lymphocytes appears to be particularly important, as it modifies secretion of cytokines, especially interleukin 2. In primary biliary cirrhosis biliary epithelial cells aberrantly express major histocompatibility complex class II antigens 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 primariy biliary cirrhosis, three patients each with autoimmune hepatitis and primary sclerosing cholangitis and nine patients with chronic viral hepatitis (five hepatitis B, four hepatitis C) using mouse monoclonal antibodies in an indirect immunoperoxidase technique. Results: In advanced primary biliary cirrhosis, HLA-DR was found 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-DR+ bile ducts also lacked expression of B7 molecules in autoimmune hepatitis. In contrast, HLA-DR, B7-1 and B7-2 were expressed simultaneously on professional antigen presenting cells such as macrophages in epitheloid granulomas. Conclusion: HLA-DR+ biliary epithelial cells in primary biliary cirrhosis insufficiently co-express B7-1 or B7-2 molecules. Therefore, they must either use different costimulatory molecules, or otherwise are deficient in lymphocyte activation. Since recognition of antigen in the absence of B7-CD28 interaction may lead to anergy of lymphoyctes, this might contribute to the impaired cytokine secretion found in primary biliary cirrhosis.