Identification of Cross Reactive Insulin Immunogenic Epitopes from Commensal Gut Microbes

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by destruction of pancreatic β-cells. Because studies suggest an environmental factor for the initiation of this autoimmunity, we hypothesized that intestinal microbes might carry peptides with sequences similarity to insulin, a major autoantigen. These peptides could modify the autoimmune response through molecular mimicry. Using a bioinformatics approach, we identified seventeen B:9-23 epitope-like sequences in different microbial proteins and investigated their capacity to stimulate insulin-specific reactive T cells obtained from T1D patients and NOD mice. In particular Parabacteroides distasonis contained a segment in the hypoxanthine phosphoribosyltransferase (HPRT) protein with high sequence similarities to the B:9-23 segment of the insulin B chain. When synthesized, this peptide stimulated both human and selected NOD mice T cells that recognized the B:9-23 peptide. Conversely, lymphocytes from mice immunized with this P. distasonis peptide showed increased secretion of cytokines when stimulated with the insulin B:9-23 peptide. P. distasonis is a commensal microbe in the human gut microbiome. Analysis of T1D metagenomic gut microbiome data from Finland, Estonia and Russia showed that the abundance of P. distasonis significantly differed between controls and seroconverting islet antibody-positive children at risk for T1D depending on the location of the study. In on-going analysis, compared to healthy control individuals, sera from T1D patients showed a significant antibody response against multiple P. distasonis proteins. In summary, a peptide from HPRT of P. distasonis, a normal component of the gut microbiome, can elicit T-cell responses cross-reactive with human insulin-related peptides. We hypothesize that such cross-reactive peptides may become accessible to intestinal phagocytes for their presentation to T cells thus modulating T1D in genetically susceptible individuals. Disclosure E. Altindis: None. A.N. Vomund: None. I. Chow: None. M. Damasio: None. W. Kwok: None. E.R. Unanue: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.