Received 7/17/97, Accepted, 8/13/97

The complex relationship between coxsackieviral infection and the development of pancreatitis is far from understood. Serologic studies that show an association between coxsackievirus infection and acute pancreatitis in humans are given additional support by the extensive data from mouse studies demonstrating that coxsackievirus B4 and B3 are tropic for the exocrine pancreas. Limited pancreatic tissue damage in patients may be compatible with tissue repair followed by full restoration of pancreatic function. Our model of CB4-P-induced acute pancreatitis in mice supports the concept of a viral etiology for acute pancreatitis in which limited tissue injury is compatible with tissue regeneration. A more complex picture emerges for idiopathic chronic pancreatitis and coxsackievirus infection. While serological studies, again, show a correlation between coxsackieviral infection and chronic pancreatitis, the exact role of viral infection in chronic disease is unclear. Whether persistent viral infection is responsible for chronic disease or whether autoimmune mechanisms are involved is currently unclear. In our model of CB4-V-induced chronic pancreatitis, autoimmune mechanisms may contribute to the tissue damage in the genetically susceptible mice. Case reports of patients with idiopathic chronic pancreatitis who generate immune responses to pancreatic antigens support the concept of autoimmunity in this disease (60-62). The group B coxsackieviruses (B4 and B3, in particular) are associated with several diseases that have an autoimmune component, eg. myocarditis (63), idiopathic dilated cardiomyopathy (63), type I insulin-dependent diabetes mellitus (6) and idiopathic chronic pancreatitis. An intriguing question is whether autoimmunity is a common characteristic of infection with the group B viruses in individuals who are genetically predisposed to an autoimmune disease.

In a discussion of chronic pancreatitis, the issue of whether this disease is a pre-malignant condition must be addressed. Can pancreatic cancer result from chronic pancreatitis? If so, what is the role of coxsackievirus infection in this process? While viral infections have not been shown to be associated with pancreatic cancer, the relationship between hepatitis B infection and the development of hepatocellular carcinoma is well established (reviewed in (64)). Chronically infected individuals with active liver disease have a high risk of developing cirrhosis and liver cancer. It is thought that the chronic liver cell injury with accompanying inflammatory and regenerative responses create the mutagenic and mitogenic stimuli necessary for the development of DNA damage that results in hepatocellular carcinoma. Does an analogous situation exist with coxsackievirus infections and pancreatic cancer? Can viral infection result in a non-autoimmune form of chronic pancreatitis that predisposes to pancreatic cancer? The possible roles of coxsackievirus infections in the development of acute pancreatitis, chronic pancreatitis, and pancreatic cancer are outlined in Figure 3.

Figure 3. A hypothetical model delineating the possible outcomes of coxsachievirus infection in the pancreas.

The relationship between coxsackieviral infection and pancreatic diseases is obviously extremely complex. The development of disease is the result of the intricate interplay between the infecting viral strain and the genetic predisposition of the host. Continued efforts to understand this complex relationship requires a multi-disciplinary approach to investigate (a) the biology of coxsackievirus replication, (b) the response of the immune system to viral infection, (c) the biology of pancreatic tissue injury and the underlying repair process and its role in the development of pancreatic cancer and (d) the generation of autoimmunity.