A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes.

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the 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 the insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these 17 peptides, the <i>hprt4-18</i> peptide, found in the normal human gut commensal <i>Parabacteroides distasonis</i>, activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with <i>P. distasonis</i> insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with <i>P. distasonis</i> accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8⁺ T cells, while decreasing FoxP3⁺ regulatory T cells. Western blot analysis identified <i>P. distasonis</i>-reacting antibodies in sera of NOD mice colonized with <i>P. distasonis</i> and human T1D patients. Furthermore, adoptive transfer of splenocytes from <i>P. distasonis</i>-treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the <i>hprt4-18</i> peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9-23-mimic peptide as a molecular trigger of T1D pathogenesis.