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bioRxiv · 10.1101/2020.10.22.350801

Parabacteroides distasonis insulin B:9-23 epitope mimic stimulates insulin specific T-cells and enhances Type 1 Diabetes in NOD mice

Huang, Q.·Chow, I.-T.·Brady, C.·Raisingani, A.·Li, D.·Ostrov, D. A.·Atkinson, M. A.·Kwok, W. W.·Kahn, C. R.·ALTINDIS, E.
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Abstract

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic {beta}-cells. One of the earliest aspects of this process is development of autoantibodies and T-cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these, one peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T-cell hybridomas from non-obese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells and destructive CD8+ T-cells, while decreasing FoxP3+ regulatory T-cells. Western blot analysis identified P. distasonis reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human infant gut microbiome data revealed that exposure of infants to P. distasonis may modulate disease pathogenesis. Taken together, these data demonstrate the potential role for an insB:9-23-mimimetic peptide from gut microbiota as a molecular trigger or modifier of T1D pathogenesis. SIGNIFICANCE STATEMENTIn Type 1 diabetes (T1D), immune cells destroy pancreatic {beta}-cells. The trigger of this response, however, is unknown. Some sequences (epitopes) in the insulin molecule form a major target for this autoimmune response. We have identified a sequence in a human gut bacterium that can mimetic this insulin epitope. Immune cells specific to insulin cross-react with this bacterial mimetic. Further, this bacterium can accelerate diabetes onset in a mouse model of T1D, inducing destructive and decreasing protective immune cells. We found this mimetic in the gut of children developing T1D. Furthermore, T1D patients have a stronger immune response to this bacterium compared to healthy individuals. Taken together, this bacterial mimetic in human gut has the potential to trigger/modify T1D onset.

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Huang, Q., Chow, I.-T., Brady, C., Raisingani, A., Li, D., Ostrov, D. A., Atkinson, M. A., Kwok, W. W., Kahn, C. R., ALTINDIS, E.. 2020-10-22. Parabacteroides distasonis insulin B:9-23 epitope mimic stimulates insulin specific T-cells and enhances Type 1 Diabetes in NOD mice. https://doi.org/10.1101/2020.10.22.350801

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