Research ArticleAutoimmunity

Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus

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Science Translational Medicine  28 Mar 2018:
Vol. 10, Issue 434, eaan2306
DOI: 10.1126/scitranslmed.aan2306

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Autoimmune initiation by bacterial antigens

Lupus patients react to many self-proteins throughout the course of disease, with some of the earliest autoantibodies targeting the RNA binding protein Ro60. Greiling and colleagues sampled the microbiota of lupus patients and detected commensals with orthologs of human Ro60. These bacterial Ro60 proteins could be recognized by patient sera and stimulated patient T cells. Colonization of germ-free mice also led to human Ro60 reactivity and lupus-like symptoms, strongly indicating that molecular mimicry of the commensal Ro60 could be triggering autoreactivity and driving disease progression. These striking results have implications beyond lupus and could help uncover global mechanisms of autoimmune pathogenesis.

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-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.

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