Bacterial amyloids from biofilms break tolerance in lupus

Abstract

Abstract Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease, in which infections are considered to play a pathogenic role, but the cellular and molecular culprits remain unknown. Bacterial biofilms are multicellular bacterial communities important in the establishment of chronic infection by pathogens. Bacteria produce amyloids, complex proteins with a conserved beta sheet structure that strengthen the extracellular matrix of their biofilms. We have reported that bacterial and eukaryotic DNA is incorporated into curli fibers, functional bacterial amyloids present in Salmonella and E. coli biofilms. I.P. infections with curli-expressing S. Typhimurium or E. coli Nissle, and also systemic administration of curli/DNA complexes purified from Salmonella biofilms accelerated onset in lupus-prone NZBxW/F1 mice and triggered autoantibodies production in non-predisposed mice, suggesting curli/DNA complexes as novel players in SLE pathogenesis. We present here evidence that curli/DNA complexes can activate multiple B cell subsets in vivo. In addition, curli/DNA complexes are capable of directly inducing in vitro polyclonal activation and proliferation of B cells from wildtype mice and from lupus-prone mice and also from 3H9 mice, which are knocked-in for a rearranged anti-DNA Ig heavy chain and whose B cells are normally tolerized for the self-Antigen. Our results suggest that curli/DNA complexes may induce autoantibody production by directly breaking tolerance in autoreactive B cell.