Beschreibung:
<jats:title>Abstract</jats:title>
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<jats:title>Introduction</jats:title>
<jats:p>The RNA-binding protein Ro60 is a primordial autoantigen in systemic lupus erythematosus (SLE), which is highly conserved across multiple species. We have previously linked anti-human Ro60 T cell and antibody responses to human commensals carrying Ro60 orthologs. Here, we tested in vivo if these autoantibodies can arise due to the murine gut microbiota in the absence of host Ro60 protein.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>Lupus-prone TLR7 tg B6 mice were crossed to Ro60 KO B6 mice and followed longitudinally for Ro60 IgG ELISAs. Littermates were treated with broad-spectrum antibiotics (vancomycin, neomycin, ampicillin, metronidazole) to determine if depletion of the gut microbiota affects anti-Ro60 autoantibody induction and disease manifestations. High-throughput 16S rRNA sequencing of the V4 region was performed on the MiSeq platform.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>TLR7 tg mice produced persistently anti-Ro60 autoantibodies despite crossing to Ro60 KO mice. Oral administration of antibiotics significantly lowered anti-Ro60 autoantibodies (n=6 each, p=0.007). 16S sequencing of antibiotics-fed mice demonstrated outgrowth of Streptophyta but suppression of taxa that may contain commensal Ro60 orthologs (Clostridiaceae, Bacteroides).</jats:p>
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<jats:title>Conclusions</jats:title>
<jats:p>Mice genetically prone to SLE-like disease can mount autoimmune responses against Ro60 even in the absence of the autoantigen. These findings suggest an antigenic trigger within the microbiota, which is supported by interventional studies with antibiotics and 16S sequencing. In summary, these studies suggest a mechanism for the development of lupus which extends beyond the known traditional risk factors.</jats:p>
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