Journal
ARTHRITIS AND RHEUMATISM
Volume 54, Issue 6, Pages 1917-1927Publisher
WILEY-BLACKWELL
DOI: 10.1002/art.21893
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Objective. To. investigate the ability of systemic lupus erythematosus (SLE) autoantigen- and Sjogren's syndrome (SS) autoantigen-associated U1 small nuclear RNA (U1 snRNA) and hY1RNA to induce interferon-alpha (IFN alpha) production. Methods. In vitro-transcribed U1 snRNA or hY1RNA and lipofectin were added to peripheral blood mononuclear cell (PBMC) cultures. Purified U1 snRNP particles and IgG from SLE patients (SLE-IgG) were added to cultures of PBMCs, enriched monocytes, or natural interferon-producing cells (NIPCs); the latter are also known as plasmacytoid dendritic cells (pDC). Cells were double-stained for IFN alpha and either blood dendritic cell antigen 2 (NIPCs/pDC) or CD14 (monocytes) and then analyzed by flow cytometry. In some experiments, RNase or inhibitors of Fc gamma receptor IIa (Fc gamma RIIa) (specific antibodies), endocytosis (chloroquine, bafilomycin A), or Toll-like receptors (TLRs; oligodeoxynucleotide 2088) were used. The produced IFNa was measured by immunoassay. Results. Lipofected U1 snRNA and hY1RNA both induced IFN alpha production in monocytes, but not in NIPC/pDC. In contrast, U1 snRNP combined with SLE-IgG induced IFN alpha production only in NIPCs/pDC, and this response was decreased by RNase treatment or inhibition of the Fc gamma RIIa, the endocytosis pathways, or the TLRs. Conclusion. Our finding that U1 snRNA and hY1RNA have IFN alpha-inducing capacity indicates that immune complexes containing such RNA, for example U1 snRNP particles, can be at least partly responsible for the ongoing IFN alpha production seen in SLE and SS. These results may help to explain the molecular mechanisms behind the pathogenesis of these and other autoimmune diseases in which autoantibodies to RNA-binding proteins occur.
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