In humans, infections with the group B coxsackieviruses (CVBs) range from asymptomatic infections to chronic, debilitating diseases. The CVBs are associated with chronic inflammatory diseases of the pancreas, heart, and central nervous system. A major focus in CVB pathogenesis is to understand the mechanisms by which these viruses cause acute diseases that resolve or acute diseases that progress to chronic diseases. The present review explores CVB infections in the development of acute and chronic pancreatitis. Mouse models of CVB-induced pancreatitis share many features with the human diseases and are providing insight into the multi-faceted processes of pancreatic tissue repair and irreversible tissue destruction. The development and progression of CVB-induced pancreatic inflammatory disease is an extremely complex process, involving both viral and host factors. The review examines the roles of the virus and host in contributing to the disease process. Recent studies of global gene expression during CVB-induced pancreatitis have increased our understanding of host factors that influence the outcome of infection and have highlighted interrelationships among complex biological programs. As we unravel the complexity of the disease process, the information gained will lead to the design of therapeutics that not only prevent the progression of chronic inflammatory disease, but that also restore functionality of affected tissues and organs.

While alcohol abuse and biliary disease can result in the development of pancreatitis, the factors that contribute to the idiopathic form of the disease are not well understood. I propose that coxsackievirus infections account for a subset of cases of pancreatitis of unknown etiology. Evidence to support this concept is derived from serological studies, case reports and animal models. In reviewing the available data, it is obvious that the relationship between coxsackievirus infection and the development of pancreatitis is not a simple one. Many elements contribute to the development of the disease including the strain of the infecting virus, the genetic predisposition of the host and additional environmental factors that maintain the disease process. 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 some serotypes (B4,B3) are tropic for the exocrine pancreas. Some viral strains may cause limited pancreatic tissue injury which is compatible with tissue repair followed by full restoration of pancreatic function. Other viral strains may cause more extensive tissue damage giving rise to chronic pancreatitis which, on a genetic background that predisposes to autoimmunity, may result in an autoimmune chronic pancreatitis. A multi-disciplinary approach is required to increase our understanding of the complex relationship between coxsackievirus infection and pancreatic diseases. Such studies should address the biology of viral replication, the immune response to infection, the role of viruses in the development of autoimmunity, the biology of pancreatic tissue injury and the underlying repair process.

While coxsackievirus infections have been linked to several autoimmune diseases, very little is known about the immunogenicity of the coxsackieviruses. Using two genetically related variants of coxsackievirus B4, CB4-P and CB4-V, the relationship between virulence and antigenicity was examined. The virulent variant, CB4-V, was shown to be more antigenic than the avirulent CB4-P variant. The increased antigenicity of CB4-V was due to a single amino acid substitution in the VP1 capsid protein (a threonine residue at amino acid position 129), a site that had been previously identified as a major determinant of viral virulence. Thr-129 of VP1 is predicted to lie within a conformational B cell epitope. In addition, a nearby linear B cell epitope spanning residues 68 to 82 of VP1 was identified as a potential serotype-specific, neutralization antigenic site. The linear and conformational B cell epitopes of coxsackievirus B4 may be analogous to antigenic sites 1 and 1B of poliovirus. To address whether the increased antigenicity of CB4-V influenced the severity of disease, mouse strains that differ in their outcome to viral infection were analyzed. Mice that developed the most severe disease and succumbed to infection were more immunoresponsive than mice that survived infection with CB4-V. The data suggest that immune-mediated mechanisms play a role in the severity of CB4-V induced disease.