Echovirus Epidemics, Autoimmunity, and Type 1 Diabetes

Type 1 diabetes mellitus [T1D] results from the autoimmune destruction of insulinproducing beta cells triggered by environmental factors (Hyoty & Taylor, 2002; Jun & Yoon, 2003). Genetic predisposition accounts for 36-50% of disease susceptibility as demonstrated in monozygotic twin studies (Barnett et al., 1981; Hemminki et al., 2010; Redondo et al., 2001). Differences in the incidence of T1D among countries are thought to be due to the proportions of HLA susceptibility haplotypes; however, other genes seem to be involved in conferring risk. On the other hand, the bulk of new T1D cases lack family history of the disease, altogether indicating that the contribution of exogenous factors to disease pathogenesis is important. Among examined environmental agents, human enteroviruses (HEVs) seem to play a prominent role (Hyoty & Taylor, 2002). HEVs are common RNA viruses spreading through the fecal-oral route. The genus comprises over 100 different virus types (Simmonds, 2006). The positive sense single-stranded 7.5 kb RNA genome contains a single open reading frame flanked by two untranslated regions (termed 5` and 3` UTRs). A translated single poly-protein is cleaved generating four structural proteins (VP1, VP2, VP3 to VP4) and seven nonstructural proteins (2A, 2B, 2C and 3A, 3B, 3C, 3D). VP1 to VP4 proteins form the viral capsid comprising epitopes involved in virus neutralization; they are responsible for the type-specific protective immunity. Nonstructural proteins determine virus replication and cellular pathology (Agol, 2006). Although prediction of T1D using genetic, immunologic, and biochemical markers is rather accurate (Hirai et al., 2008; Notkins, 2007), the cost-benefit ratio of periodical determinations appears not to justify large scale screening programs. Unfortunately, primary, secondary and tertiary prevention strategies evaluated so far have failed to prevent or halt the initiation or progression of the disease. For instance, attempts to induce disease regression by utilizing either immunosuppressive and/or cell replacement therapies have been successful only temporarily (Shapiro et al., 2006; Voltarelli et al., 2007). A vaccine inducing neutralization of putative pathogenic HEVs may represent an ideal primary prevention means for T1D. Unfortunately, available data on sequence of HEV isolated from pancreases of patients who died at T1D onset are not sufficient to define the