Type 1 diabetes (T1D) is an autoimmune disorder that results from T cell-mediated destruction of the insulin-producing β cells of the pancreatic islets. Accumulating evidence from both human and animal studies points to the gut microbiome, the 100 trillion microbes inhabiting our intestinal tract, as a key component driving the inflammatory processes leading to T1D. However, the mechanisms therein are poorly understood. We propose that this inflammatory milieu occurs in the pancreas, where microbes or microbial fragments that translocate from their usual luminal, mucosal sites persist and induce the cytokine and chemokine signals needed for destructive, autoimmune cellular and humoral responses that destroy the insulin producing β cells. By controlling this inflammation via vaccination against a highly conserved microbial surface antigen, poly-N-acetyl glucosamine (PNAG), we can decrease the inflammatory response such that vaccination prevents diabetes. In analyses of human and murine pancreatic islets, we have found that PNAG is readily detectable within diabetic, but not healthy, pancreases and associated with both T cells and polymorphonuclear cells (PMNs). This finding suggests that inducing an effective immune response that can clear PNAG-containing microbes or microbial fragments may be critical in counteracting the microbiota-driven inflammation leading to autoimmunity. We report that NOD female mice vaccinated against PNAG exhibited a drastic reduction in diabetes incidence from in 70% of 21 controls to 17% of 18 PNAG-immune mice. Immunophenotyping on these mice indicates that PNAG vaccination dramatically increases Foxp3+ Tregs as well as CD4+ and CD4- IL-10-producing cells. Taken together, our work provides evidence that the translocation of microbial antigens to the pancreas may drive inflammation leading to T1D, and that vaccination against one particular microbial antigen, PNAG, may lead to protection against this disease.
A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc.
American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-13 to A.K.)