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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 immunoprecipitated 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., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

An RNA-binding protein, the Ro 60 kDa autoantigen, is a major target of the immune response in patients suffering from two systemic rheumatic diseases, systemic lupus erythematosus and Sjogren's syndrome. In lupus patients, anti-Ro antibodies are associated with photosensitive skin lesions and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with photosensitive skin lesions and a cardiac conduction defect, third degree heart block. In vertebrate cells, the Ro protein binds small RNAs of unknown function known as Y RNAs. Although the cellular function of Ro has long been mysterious, recent studies have implicated Ro in two distinct processes: small RNA quality control and the enhancement of cell survival following exposure to ultraviolet irradiation. Most interestingly, mice lacking the Ro protein develop an autoimmune syndrome that shares some features with systemic lupus erythematosus in patients, suggesting that the normal function of Ro may be important for the prevention of this autoimmune disease. In this review, we summarize recent progress towards understanding the role of the Ro 60 kDa protein and discuss whether the cellular function of Ro could be related to certain manifestations of lupus in patients., (Copyright 2004 Springer-Verlag)

The Ro 60 kDa autoantigen, an RNA binding protein, is a major target of the immune response in patients with systemic lupus erythematosus. As mice lacking Ro develop a lupus-like syndrome, Ro may be important for preventing autoimmunity. However, the cellular function of Ro, which binds small cytoplasmic RNAs of unknown function called Y RNAs, has been enigmatic. Ro has been proposed to function in 5S rRNA quality control based on experiments in Xenopus laevis oocytes, and a Ro ortholog enhances survival of the eubacterium Deinococcus radiodurans after ultraviolet irradiation. To test the general importance of these two observations for Ro function, we investigated the role of Ro in mammalian cells. We report that, in mouse embryonic stem (ES) cells, Ro binds variant spliceosomal U2 snRNAs. Expression of mouse U2 snRNAs in Xenopus oocytes reveals that binding occurs in nuclei and appears to involve recognition of misfolded RNA. Moreover, mouse ES cells lacking Ro exhibit decreased survival after ultraviolet irradiation. In irradiated cells, both Ro and a Y RNA accumulate in nuclei. We propose that Ro plays a general role in small RNA quality control and that this function is important for cell survival after ultraviolet irradiation.

Antibodies against a conserved RNA-binding protein, the Ro 60-kDa autoantigen, occur in 24-60% of all patients with systemic lupus erythematosus. Anti-Ro antibodies are correlated with photosensitivity and cutaneous lesions in these patients and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with complete congenital heart block and photosensitive skin lesions. In higher eukaryotes, the Ro protein binds small RNAs of unknown function known as Y RNAs. Because the Ro protein also binds misfolded 5S rRNA precursors, it is proposed to function in a quality-control pathway for ribosome biogenesis. Consistent with a role in the recognition or repair of intracellular damage, an orthologue of Ro in the radiation-resistant eubacterium Deinococcus radiodurans contributes to survival of this bacterium after UV irradiation. Here, we show that mice lacking the Ro protein develop an autoimmune syndrome characterized by anti-ribosome antibodies, anti-chromatin antibodies, and glomerulonephritis. Moreover, in one strain background, Ro-/- mice display increased sensitivity to irradiation with UV light. Thus, one function of this major human autoantigen may be to protect against autoantibody development, possibly by sequestering defective ribonucleoproteins from immune surveillance. Furthermore, the finding that mice lacking the Ro protein are photosensitive suggests that loss of Ro function could contribute to the photosensitivity associated with anti-Ro antibodies in humans.

Summary: Many bacteria contain an ortholog of the Ro autoantigen, a ring-shaped protein that binds noncoding RNAs (ncRNAs) called Y RNAs. In the only studied bacterium, Deinococcus radiodurans, the Ro ortholog Rsr functions in heat-stress-induced ribosomal RNA (rRNA) maturation and starvation-induced rRNA decay. However, the mechanism by which this conserved protein and its associated ncRNAs act has been obscure. We report that Rsr and the exoribonuclease polynucleotide phosphorylase (PNPase) form an RNA degradation machine that is scaffolded by Y RNA. Single-particle electron microscopy, followed by docking of atomic models into the reconstruction, suggests that Rsr channels single-stranded RNA into the PNPase cavity. Biochemical assays reveal that Rsr and Y RNA adapt PNPase for effective degradation of structured RNAs. A Ro ortholog and ncRNA also associate with PNPase in Salmonella Typhimurium. Our studies identify another ribonucleoprotein machine and demonstrate that ncRNA, by tethering a protein cofactor, can alter the substrate specificity of an enzyme. [ABSTRACT FROM AUTHOR]