Coxsackievirus immunization delays onset of diabetes in non-obese diabetic mice.

Enteroviruses may be involved in the pathogenesis of Type 1 diabetes through different mechanisms including triggering of autoimmunity. The effect of immunization with coxsackievirus B4-E2 on diabetes incidence was studied in the non-obese diabetic mice, an animal model for human autoimmune insulin-dependent diabetes mellitus. The immunization delayed the onset of diabetes in the mice, and the effect was mediated at least partially by virus immunization-activated splenocytes as demonstrated by adoptive transfer experiments. Immunization resulted in a strong humoral immune response against the immunizing virus, formalin-inactivated coxsackievirus B4-E2. Cell-mediated immune response to virus antigen was characterised by interferon gamma and interleukin 10 secretion. The immunization also resulted in increased antibody levels against several beta-cell autoantigens. By using epitope mapping we were able to show that in addition to reactivity with the known epitopes of viral proteins and tyrosine phosphatase IA-2 or heat shock protein 60, responses to some other regions of autoantigens were enhanced. In preproinsulin, the response was restricted against an antigenic region earlier identified as DR4-dependent epitope. This reactivity can not be explained by homologous amino acid sequences and it is possible that enterovirus immunization might change the autoantigen specific TH1/TH2 balance in non-obese diabetic mice. In conclusion, our results suggest that coxsackievirus immunization increased humoral immune response to beta cell autoantigens and this was associated with a less destructive pathology for spontaneous diabetes in non-obese diabetic mice.

Enterovirus infection can induce immune responses that cross-react with beta-cell autoantigen tyrosine phosphatase IA-2/IAR.

Insulin-dependent (type 1) diabetes is characterized by progressive destruction of insulin-producing beta cells probably by autoreactive T lymphocytes. Viral infections, especially those caused by coxsackieviruses, are postulated to play a role in the pathogenesis of the disease in humans. One mechanism by which viral infections could initiate or accelerate diabetogenic processes is "molecular mimicry," induction of antiviral immune responses cross-reacting with epitopes in the beta-cell autoantigens. Tyrosine phosphatases (IA-2, IAR) represent a major target autoantigen in type 1 diabetes. Both humoral and cellular immune responses are directed to the carboxy-terminal (C-terminal) part of the protein. This region has a 5-amino acid sequence identity, followed by five amino acid similarity with the conservative motif in the VP1-protein of enteroviruses (PALTAVETGA/HT), which is a highly immunogenic B- and T-cell epitope in enterovirus infection-induced immune responses. This observation prompted us to investigate potential humoral cross-reactions between immune responses induced by tyrosine phosphatases and enteroviruses. The reactivities of various peptide- and virus-induced rabbit antisera clearly demonstrated that cross-reactions do exist, and in both directions. Using epitope mapping, we were able to show that several diabetes-linked epitopes in IA-2 were also recognized by CBV-4-induced antisera. Immunization of female NOD-mice with formalin-inactivated purified strain of coxsackievirus B4 (CBV-4-E2) induced an immune response that recognized the IA-2/IAR diabetogenic peptide. The results obtained with human paired sera, collected during enterovirus infection, indicated that enterovirus infection in humans may also occasionally induce a humoral response that cross-reacts with IA-2/IAR.