The role of viruses in type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals.
Type I (insulin-dependent) diabetes mellitus results from the progressive loss of pancreatic beta cells. Environmental factors are believed to play an important part in the development of Type I diabetes by influencing the penetrance of diabetes susceptibility genes. As one environmental factor, the virus has long been considered to play a part in this disease. To date 13 different viruses have been reported to be associated with the development of Type I diabetes in humans and in various animal models. The most clear and unequivocal evidence that a virus induces diabetes in animals comes from studies on the D variant of the encephalomyocarditis (EMC-D) virus in mice and the Kilham rat virus (KRV) in rats. The infection of genetically susceptible strains of mice with a high titre of EMC-D virus results in the development of diabetes within 3 days. This is largely due to the rapid destruction of beta cells by the replication of the virus within the beta cells. In contrast, the infection of mice with a low titre of EMC-D virus results in a limited replication of the virus before the induction of neutralizing anti-virus antibody and the subsequent recruitment of activated macrophages. The Src kinases, particularly hck, play an important part in the activation of macrophages and the subsequent production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and nitric oxide (NO), leading to the destruction of beta cells which results in the development of diabetes. The Kilham rat virus causes autoimmune diabetes in diabetes resistant (DR)-BB rats without infection of beta cells. The infection of DR-BB rats with KRV results in the disruption of the finely tuned immune balance of Th1-like CD45RC+CD4+ and Th2-like CD45RC-CD4+ T cells, leading to the selective activation of beta-cell-cytotoxic effector T cells.
Jun
H S
HS
Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Yoon
J W
JW
D000818:Animals; D018188:Cardiovirus Infections / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology* / Q000821:virology*; D004195:Disease Models, Animal; D004686:Encephalomyocarditis virus / Q000502:physiology; D006801:Humans; D007515:Islets of Langerhans / Q000821:virology; D051379:Mice; D010322:Parvoviridae Infections / Q000150:complications; D017992:Parvovirus / Q000502:physiology; D051381:Rats; D014779:Virus Replication