Elsevier

Clinical Immunology

Volume 117, Issue 3, December 2005, Pages 238-250
Clinical Immunology

Association of anti-nucleoprotein autoantibodies with upregulation of Type I interferon-inducible gene transcripts and dendritic cell maturation in systemic lupus erythematosus

https://doi.org/10.1016/j.clim.2005.07.009Get rights and content

Abstract

Lupus patients selectively produce autoantibodies against nucleoproteins. Since the RNA/DNA components of these autoantigens are endogenous TLR ligands capable of stimulating Type I interferon (IFN-I) production, we asked whether autoantibodies against the ribonucleoproteins Sm/RNP and Ro60 and double-stranded DNA are associated with high levels of IFN-I. IFN-I levels were increased in SLE (n = 88) vs. other autoimmune diseases (n = 82) and controls (n = 57) (P < 0.0001) and were associated positively with autoantibodies against Sm/RNP, Ro60/La, and dsDNA but negatively with anti-phospholipid. Low numbers of circulating plasmacytoid and myeloid dendritic cells also were associated with these autoantibodies. The IFN-I and dendritic cell abnormalities correlated with disease severity and were not therapy-related. These findings suggest that immunostimulatory nucleic acid components of autoantigens may act as endogenous adjuvants by promoting IFN-I production and dendritic cell maturation, helping to explain the high prevalence of autoantibodies against nucleoprotein antigens in SLE.

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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