Association of anti-nucleoprotein autoantibodies with upregulation of Type I interferon-inducible gene transcripts and dendritic cell maturation in systemic lupus erythematosus
Introduction
Most SLE patients produce autoantibodies against ribonucleoproteins, such as the Sm/RNP, Ro (SS-A), and La (SS-B) antigens, or deoxyribonucleoproteins such as chromatin [1], [2], [3], [4]. It is unclear why nucleoproteins are selectively targeted for an autoimmune response. We recently reported that the U1 and Y1–5 RNA components of the Sm/RNP and Ro60 antigens, respectively, stimulate production of Type I interferons (IFN-I) and dendritic cell maturation, hallmarks of the adjuvant effect (K. Kelly et al., submitted).
The Type I interferons IFNα and IFNβ are powerful adjuvants that promote dendritic cell maturation as well as primary and memory B cell responses [5]. Precursors of plasmacytoid dendritic cells (PDCs), the most important IFN-I producing cells, represent ∼0.5% of peripheral blood mononuclear cells (PBMCs) [6], [7] and express IL-3 receptors (CD123) and MHC class II, but not CD11c or other lineage (lin) markers [6], [8]. Myeloid dendritic cell (MDC) precursors (CD11c+, CD123−, class II+, lin−) also circulate [9] and undergo maturation in response to IFN-I [10], [11]. The maturation state of MDCs regulates the outcome of antigen presentation: tolerance is induced by self-antigens presented by immature MDCs and adaptive immune responses by foreign antigens presented by mature MDCs activated by “danger signals” such as Toll-like receptor (TLR) ligands [12]. Among the microbial substances known to promote dendritic cell maturation are immunostimulatory nucleic acids, which are recognized by molecular pattern receptors because they are not expressed normally by eukaryotic cells or because they are expressed in abnormal locations. Double-stranded (ds) RNA and certain single-stranded (ss) RNAs are ligands for TLR3 and TLR7/8, respectively [13], [14], [15], [16], and methylated CpG DNA sequences are ligands for TLR9 [17]. Engagement of Toll-like receptors by these nucleic acid ligands stimulates IFN-I production through MyD88-dependent and MyD88-independent pathways [18]. Since nucleoproteins carry endogenous TLR ligands in the form of their associated nucleic acids, it was of interest to see if autoantibodies against the Sm/RNP, Ro (SSA), and chromatin (dsDNA) autoantigens are associated with high levels of IFN-I.
Section snippets
Subjects
Subjects seen at the University of Florida Center for Autoimmune Disease were classified as having SLE, scleroderma, Sjogren's syndrome, polymyositis/dermatomyositis, rheumatoid arthritis, mixed connective tissue disease, or undifferentiated connective tissue disease) using established criteria [19]. Patient demographics are summarized in Table 1. Disease activity was assessed by SLEDAI, and renal disease was scored as described [20]. Subjects were questioned about viral or bacterial infections
Results
Because the administration of exogenous IFNα is associated with antinuclear antibody production [22], [23], we investigated the relationship between circulating IFN-producing cells, IFN-I production, and the formation of autoantibodies associated with SLE.
Discussion
Autoantibodies to small ribonucleoproteins, such as the U1, U2, U4–6, and U5 small nuclear ribonucleoproteins (snRNPs) and the cytoplasmic Ro60 (Y1–Y5) ribonucleoproteins are strongly associated with systemic autoimmune diseases such as SLE and Sjogren's syndrome [1], [2], [3]. Over half of lupus patients produce autoantibodies against one or more of these antigens, and as many as 70% produce anti-dsDNA antibodies [4], [29]. Levels can be extraordinarily high, sometimes approaching 20% of the
Acknowledgments
This work was supported by research grants R01-AR40391 and M01-R00082 from the US Public Health Service, State of Florida funds to the Center for Autoimmune Diseases, and generous gifts from Lupus Link, Inc. (Daytona Beach, FL) and Mr. Lewis M. Schott. We thank Marlene Sarmiento, Annie Chan, Frances Reeves, and Lisa Oppel for clinical assistance, Minna Honkanen-Scott for expert technical assistance, and Gina Tonogbanua for helping with manuscript preparation.
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