Immunogenecity of <i>Mycobacterium avium</i> subsp. <i>paratuberculosis</i> epitopes cross-reacting with human ZnT8 and proinsulin peptides in autoimmune diabetes

Although numerous studies put in evidence the increasing incidence of type 1 diabetes (T1D), its cause remains unclear. The role of Mycobacterium avium subsp. paratuberculosis (MAP) as a putative environmental agent triggering or accelerating the disease has been previously hypothesized in Sardinian and Italian T1D populations. The present thesis further sustains this association by reporting an elevated seroreactivity to MAP-derived epitopes and homologous human peptides corresponding to proinsulin and ZnT8 fragments in populations at different T1D stages and originating from distinct biogeographic backgrounds. Anti-MAP antibodies (Abs) resulted detectable in the first months of life before the appearance of classical autoantigens and, in most cases, were maintained in time making the selected peptides good candidates for early biomarkers. Likewise, Abs responses to the same antigens were observed among LADA patients and subjects affected by Hashimoto’s thyroiditis which frequently complicates T1D. Validation with a MAP-specific lipopentapeptide confirmed these results in coincidence with a stable Abs status. In PBMC primary culture, ZnT8 peptide and its MAP homolog induced the expression of proinflammatory cytokines along with increased cell-mediated responses and apoptosis. Good correlation between values obtained for the homologous MAP/human peptide pairs point at cross-reactivity through which mechanisms of self tolerance may be disrupted leading to autoimmunity