Antibodies Recognizing Mycobacterium avium paratuberculosis Epitopes Cross-React with the Beta-Cell Antigen ZnT8 in Sardinian Type 1 Diabetic Patients

Abstract

The environmental factors at play in the pathogenesis of type 1 diabetes (T1D) remain enigmatic. Mycobacterium avium subspecies paratuberculosis (MAP) is transmitted from dairy herds to humans through food contamination. MAP causes an asymptomatic infection that 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 asked 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 an enzymatic immunoassay. 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.

Detection of Mycobacterium avium subsp. paratuberculosis in Iranian patients with type 1 diabetes mellitus by PCR and ELISA

“…This similarity may cause autoimmunity by molecular mimicry between MAP antigens and pancreatic islet β-cells, and trigger islet cell depletion. These results are in line with previous studies performed in Sardinia [19,26].…”

“…The association of MAP with T1DM has been reported in Sardinia, known to have a high prevalence of type 1 diabetes and a high rate of MAP infection among sheep and cattle [6][7][8]19,27]. However, Rani et al could not find any association despite the high prevalence of MAP and T1DM in India, probably due to the low number of patients investigated [21] or the genetic predisposition of the infected population in developing such an autoimmunity.…”

“…In addition, MAP has been suggested as a possible cause of T1DM. The association of T1DM and MAP has been observed in the Sardinian population (Italy) [19,20], but a recent study could not replicate this finding in India, probably due to the small number of investigated samples [21].…”

“…The procedure was performed as previously described [19]. The optical density (OD) was read at a 405 nm wavelength using VersaTunable MAX microplate reader (Molecular Devices, Sunnyvale, USA).…”

Virulence and Immunity Orchestrated by the Global Gene Regulator sigL in Mycobacterium avium subsp. paratuberculosis

“…paratuberculosis represents a major threat to dairy cattle (4,6) with the potential to spread to humans (39)(40)(41)(42)(43). Earlier reports indicated that M. avium subsp.…”