Hepatitis B and C viruses; new research has recently emerged in this area. “New data indicates that when you express the whole genome of a virus in the liver of a mouse, you can induce liver cancer with a very long latency – it takes two years – even in the absence of overt lymphocytic inflammation,” says Professor Heikenwälder. “This clearly indicates that the viral proteins have some oncogenic potential themselves. But it’s believed that the viral infection is very persistent. That matters in this particular case – the persistence of the virus infection drives an inflammatory reaction that then turns on the whole cascade.” Researchers can look at the early stages of this process through analysis of tissue from mice. It is thought that lymphocytes play an important role in driving the inflammatory process, while there is a signalling pathway in hepatocytes that drives liver cancer. “This indicates that
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maybe the starting point of inflammation is actually the hepatocyte, that it somehow induces inflammation. Various techniques have shown that, in human patients infected with Hepatitis B and C viruses, it is actually the hepatocytes at the very beginning that start to express chemokines and cytokines. So these inflammatory molecules attract immune cells and that inflammation is actually needed to some extent for the virus to replicate efficiently,” says Professor Heikenwälder. Chronic inflammation also induces the killing of hepatocytes – and that in turn causes compensation, which leads on to further problems. “This causes fibrosis, it causes hepatocytes to proliferate more often than they actually want to,” continues Professor Heikenwälder. “Hepatocytes are usually in the dormant cell cycle state – called G0. They don’t like it if they are pushed into a cell cycle where they have to go through various other phases.”
These problems do not occur in acute inflammation, as the initial cause of the problem is resolved; the antigen is not there any more, the cytokines are not expressed and the hepatocytes can regenerate. However, with chronic inflammation, lymphoid-tissue like structures start to develop. “They present antigens, get activated, colonially expand and then leave again in the circulation to produce antibodies. These chronic inflammatory structures look almost identical, or certainly very similar, to what you can find in the secondary lymphoid tissue,” says Professor Heikenwälder. Chronic inflammation can also have an impact on other organs; Professor Heikenwälder points to the example of auto-immune pancreatitis. “This is a chronic inflammatory auto-immune reaction in the pancreas, it also forms another chronic inflammatory structure. As a consequence of this, high amounts of antibodies are secreted into the serum, and
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