Salmonella infection induces autoantibody production in MyD88-deficient host: Identification of candidate bacterial proteins with homology to murine antigens

Abstract

Abstract Persistent bacterial infections have been causally linked to the development of autoimmune diseases, but the precise mechanisms underlying this remain largely unknown. Of note, we demonstrated that systemic infection by attenuated Salmonella enterica serovar Typhimurium induces a breakdown in B cell tolerance in MyD88-deficient mice, as evidenced by the production of autoantibodies to nuclear and cytoplasmic antigens and immune complex deposition in the kidneys. The splenic niche of infected MyD88−/− mice revealed increased counts of activated myeloid cell subpopulations as well as CD4+ and CD8+ T cells. Moreover, this was associated with increased Th21 cell differentiation and the appearance of CD4+ T cells co-expressing IFN-g/IL-4 and IFN-g/IL-10. Importantly, infection with other bacteria (e.g. Acinetobacter baumanii, Streptococcus agalactiae or Escherichia coli) was unable to trigger the autoimmune phenomenon. We reasoned that the autoimmune response could be triggered by a process of molecular mimicry between mouse and Salmonella proteins. Bioinformatic analysis was used to identify potential Salmonella antigens with a high degree of homology to mouse proteins. This analysis revealed several candidate bacterial proteins with high homology to murine immune system proteins. The identified bacterial proteins were all uniquely expressed by Salmonella but not by the other three bacterial species that were incapable of inducing the autoimmune response in MyD88−/− mice. Therefore, our data suggest a mechanism for pathogen-specific induction of autoantibody production in the absence of MyD88 signaling pathway and provide important clues concerning the genotype-environmental factor correlations.