Cross-reactive Immune Responses between Enteroviruses and Islet Cell Autoantigens Härkönen, Taina, Cross-reactive Immune Responses between Enteroviruses and Islet Cell Autoantigens

Previous scientific data suggests that enterovirus infections, especially those caused by coxsackieviruses have a role in the pathogenesis of type 1 diabetes. One mechanism by which viral infection could initiate or accelerate diabetogenic process in humans is ‘molecular mimicry’, induction of antiviral immune responses which cross-react with self-epitopes in insulin producing β-cells. This study was prompted by sequence homology discovered between enterovirus capsid/procapsid proteins VP1 and VP0 and two immunogenic diabetes-associated epitopes in β-cell autoantigens IA-2/IA-2β and HSP60. Possible cross-reactive immune responses were investigated using proteins and peptides derived from the homologous regions and extended to sera obtained with immunization with viral proteins and those derived from viral infections. Our results showed that rabbit antibodies raised against HSPs recognized capsid protein VP1 of coxsackievirus A9 (CAV9) and coxsackievirus B4 (CBV4) and recombinant VP1 protein of CAV9. The results obtained with VP1-, VP0and IA-2-peptide induced rabbit antisera demonstrated that immunization of rabbits with these peptides induce cross-reacting immune responses. Among the cross-reactive immune responses studied, results obtained with coxsackievirusderived VP1-peptide and IA-2-peptide induced antisera were most convincing. Enterovirus induced humoral responses were further studied in rabbits and NOD mice, which is an animal model for human type 1 diabetes. Both CBV4and CAV9-induced rabbit antisera reacted with immunogenic epitope in IA-2. Immunization of female NOD mice with the diabetes-associated strain CBV4-E2 resulted in recognition of epitopes in viral capsid proteins. Epitope mapping with partially overlapping peptides in CAV9 capsid proteins demonstrated that recognition of both VP0 and VP1 peptide sequences was prominent. Furthermore, epitope mapping of islet cell autoantigens showed that regions in IA-2 and HSP60, with sequence similarity with VP1 and VP0, were both recognized by CBV4-E2 immunized NOD mice. Studies were further extended to humans. Our results indicate that enterovirus infections in humans may induce immune responses that cross-react with β-cell autoantigens.