Mycobacterium aviumsubsp.paratuberculosisprotein MAP 3865c may mimic the pancreatic islet autoantigen Znt8 relevant in type 1 diabetes

The environmental factors at play in the pathogenesis of type 1 diabetes (T1D) remain enigmatic.Mycobacterium aviumsubspeciesparatuberculosis(MAP) is transmitted from dairy herds to humans through food contamination. MAP causes an asymptomatic infection which is highly prevalent in Sardinian T1D patients compared with type 2 diabetes (T2D) and healthy controls. Moreover, MAP elicits humoral responses against several mycobacterial proteins. We searched whether antibodies (Abs) against one of these proteins, namely MAP3865c, which displays a sequence homology with the β-cell protein zinc transporter 8 (ZnT8) could be cross-reactive with ZnT8 epitopes. To this end, Ab responses against MAP3865c were analyzed in Sardinian T1D, T2D and healthy subjects using indirect ELISA. Abs against MAP3865c recognized two immunodominant transmembrane epitopes in 52-65% of T1D patients, but only in 5-7% of T2D and 3-5% of healthy controls. There was a linear correlation between titers of anti-MAP3865c and anti-ZnT8 Abs targeting these two homologous epitopes, and pre-incubation of sera with ZnT8 epitope peptides blocked binding to the corresponding MAP3865c peptides. These results demonstrate that Abs recognizing MAP3865c epitopes cross-react with ZnT8, possibly underlying a molecular mimicry mechanism which may precipitate T1D in MAP-infected individuals.