Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of E. gallinarum in tissues, and eliminated pathogenic autoantibodies and Tcells. Hepatocyte–E. gallinarum cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by an intramuscular vaccine targeting the pathobiont. E. gallinarum–specific DNA was recovered from liver biopsies of autoimmune patients, and cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans. These discoveries show that a gut pathobiont can translocate and promote autoimmunity in genetically predisposed hosts.

Dendritic cells (DCs) control the balance between effector and regulatory T cells in vivo. Hence, the study of DCs might identify mechanisms of disease pathogenesis and guide new therapeutic approaches for immune-mediated disorders. We found that IL-27 signaling in murine DCs limits the generation of effector TH1 and TH17 cells and the development of experimental autoimmune encephalomyelitis (EAE). The effects of IL-27 were mediated, at least partially, through the induction of the immunoregulatory molecule ENTPD1 (CD39) in DCs. IL-27-induced ENTPD1 decreased extracellular ATP levels, down-regulating nucleotide-dependent NLRP3 inflammasome activation. Finally, therapeutic vaccination with IL-27-conditioned DCs suppressed established relapsing-remitting EAE. Thus, IL-27 signaling in DCs limits pathogenic T cell responses and the development of autoimmunity.

Summary Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using a Toll-like receptor 7 (TLR7)-dependent mouse models of lupus, we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated via dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of Lactobacillus reuteri in mice and fecal enrichment of Lactobacillus in a subset of lupus patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that mediates interferon pathways implicated in the pathogenesis of human autoimmunity.

The earliest autoantibodies in lupus are directed against the RNA binding autoantigen Ro60, but the triggers against this evolutionarily conserved antigen remain elusive. We identified Ro60 orthologs in a subset of human skin, oral, and gut commensal bacterial species and confirmed the presence of these orthologs in patients with lupus and healthy controls. Thus, we hypothesized that commensal Ro60 orthologs may trigger autoimmunity via cross- reactivity in genetically susceptible individuals. Sera from human anti-Ro60–positive lupus patients immunoprecipi-tated commensal Ro60 ribonucleoproteins. Human Ro60 autoantigen–specific CD4 memory T cell clones from lupus patients were activated by skin and mucosal Ro60-containing bacteria, supporting T cell cross-reactivity in humans. Further, germ-free mice spontaneously initiated anti-human Ro60 T and B cell responses and developed glomerular immune complex deposits after monocolonization with a Ro60 ortholog–containing gut commensal, linking anti- Ro60 commensal responses in vivo with the production of human Ro60 autoantibodies and signs of autoimmunity. Together, these data support that colonization with autoantigen ortholog-producing commensal species may initiate and sustain chronic autoimmunity in genetically predisposed individuals. The concept of commensal ortholog cross-reactivity may apply more broadly to autoimmune diseases and lead to novel treatment approaches aimed at defined commensal species.