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The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression

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Science  23 Oct 2015:
Vol. 350, Issue 6259, pp. 455-459
DOI: 10.1126/science.aac7442

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An Aluring new autoantibody target

Autoimmunity is the immune system's ultimate act of betrayal. Cells designed to protect against invading microbes suddenly target the host instead. In the autoimmune disease systemic lupus erythematosus, antibodies target DNA and host proteins, including the RNA binding protein Ro60. Hung et al. discovered that Ro60 bound to endogenous Alu retroelements. They detected antibody-Ro60-Alu RNA immune complexes in the blood of individuals with lupus and an enrichment of Alu transcripts. Ro60 bound to Alu probably primes RNA-binding innate immune receptors within B cells, leading these cells to make antibodies that target Ro60-Alu RNA and drive disease-causing inflammation.

Science, this issue p. 455

Abstract

Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren’s syndrome. However, it is unclear whether Ro60 and its associated RNAs contribute to disease pathogenesis. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60–positive SLE immune complexes contained Alu RNAs, and Alu transcripts were up-regulated in SLE whole blood samples relative to controls. These findings establish a link among the lupus autoantigen Ro60, Alu retroelements, and type I interferon.

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