Lupus T and B cell cross-reactivity between the human Ro60 autoantigen and Ro60 orthologs from the human microbiota

Abstract

Abstract Human Ro60 is an RNA binding protein that is commonly targeted in systemic autoimmunity. We identified Ro60 orthologs that are conserved in a subset of skin, oral, and gut commensal species. Since anti-Ro60 antibodies are the earliest autoantibodies detected in lupus patients, we hypothesized that commensal Ro60 orthologs may trigger autoimmunity via autoepitope cross-reactivity in genetically susceptible individuals. While Ro60-producing gut commensals were common among both healthy controls and lupus patients, only antibodies from 4 Ro60-positive lupus patients, but not Ro60-negative subjects, co-immunoprecipitated Ro60 and its bound Y RNA from the Ro60-containing skin commensal P. propionicum. This suggests antibody cross-reactivity between human Ro60 antibodies and commensal Ro60. Next, Ro60-specific CCR6+ and CCR6- CD4 memory T cells clones from lupus patients were generated using a T cell library assay. Ro60 CCR6+ T cell clones proliferated in response to P. propionicum, demonstrating T cell cross-reactivity with commensal Ro60. Finally, germ-free mice monocolonized with B. thetaiotaomicron, a Ro60 ortholog-containing gut commensal, produced fecal anti-human Ro60 IgA antibodies (n=4, p=0.04), linking anti-Ro60 commensal responses in vivo with the generation of human Ro60 autoantibodies. In summary, Ro60 autoimmune T and B cells from human lupus patients cross-reacted with commensal Ro60 in vitro and commensal Ro60 triggered anti-Ro60 antibodies in vivo. Taken together, these data suggest that colonization with autoantigen ortholog-carrying species may sustain chronic autoimmunity in patients. This concept could lead to development of novel therapeutic approaches targeted at the human microbiota.