It is thus plausible that a vicious cycle of microbial Ro60 ortholog production, UV exposure and anti-Ro60 antibody binding to first microbial, and then hRo60 promotes cutaneous manifestations in lupus patients and Ro60-positive commensals sustain systemic auto-antibodies (fig. (2.8M) GUID:?C55250F1-5C66-4027-800F-493294E78FC2 Abstract 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-Ro60Cpositive lupus patients immunoprecipi-tated commensal Ro60 ribonucleoproteins. Human Ro60 autoantigenCspecific 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 orthologCcontaining 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 EP 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 PF-04620110 lead to novel treatment approaches aimed at defined commensal species. INTRODUCTION Systemic lupus erythematosus (SLE) is a chronic, debilitating, multi-organ autoimmune disease with unclear etiology. Almost all patients with SLE have high titers of anti-nuclear autoantibodies, which can be detected years before the onset of symptoms (1). Anti-Ro antibodies are present in about 50% of patients with SLE, up to 90% of patients with subacute cutaneous lupus erythematosus (SCLE), 90% of newborns with neonatal lupus erythematosus (NLE) (2), and up to 80% of patients with Sj?grens syndrome. Two distinct Ro antigens have been identified, Ro60 and Ro52, which differ substantially in structure and function. Although both antibodies can be found in patients with SLE, anti-Ro60 is the earliest and most common preclinical anti-nuclear antibody (1, 3). In addition, anti-Ro antibodies are pathogenic, as evidenced by the trans-placental spread of these antibodies in NLE, leading to potentially fatal cardiac conduction defects and cutaneous lesions similar to SCLE (4C7). Hence, identifying targetable triggers of anti-Ro60 antibodies would be beneficial for alleviating a variety of lupus manifestations and provide new insights into the pathogenesis of this disease. The fact that the incidence of SLE has tripled in the last 50 years underscores the need for fundamentally new approaches and also suggests that genetic factors alone may not be sufficient to explain disease pathology. The Ro60 protein is a ring-shaped RNA binding protein that forms ribonucleoprotein (RNP) complexes with ~100-nucleotide noncoding RNAs (ncRNAs) called Y RNAs. Because Ro60 also binds certain mis-folded ncRNAs, it is proposed to function in ncRNA surveillance (5). A recent study suggests that endogenous Alu retroelements are also Ro60 targets in human cells (8). Most human anti-Ro60 autoantibodies bind epitopes that overlap with the RNA binding sites (6). Ro60 appears to PF-04620110 have an important role in the environmental stress response; mammalian and bacterial cells lacking Ro60 are more sensitive to ultraviolet (UV) irradiation (9, 10), similar to the UV sensitivity seen in lupus patients. Immunization against human Ro60 (hRo60) protein in mice leads to intermolecular epitope spreading with subsequent production of antibodies against Ro52, La, Smith, and U1RNP (11), providing further evidence for the role of early anti-Ro60 auto-antibodies in disease initiation and progression in systemic autoimmunity. PF-04620110 Mice lacking Ro60 develop a lupus-like syndrome with autoantibodies, nephritis, and photosensitivity (12), possibly due to the pathogenic accumulation of defective and excess ncRNAs and subsequent activation of Toll-like receptors (TLRs) (13). Thus, identifying targetable triggers of anti-Ro60 autoimmunity may improve our understanding of the pathogenesis of lupus, may serve as a paradigm for other systemic autoimmune diseases, and could be useful for developing therapies that prevent.