Abstract
BackgroundPristane-treated mice chronically produce high levels of anti-ribonucleoprotein/Smith (anti-Sm/RNP) and other lupus autoantibodies. The present study addressed how these autoantibody levels are maintained over time.MethodsLupus was induced in BALB/c mice using pristane. Naïve B cells, switched memory B cells, switched plasmablasts, and plasma cells were flow-sorted and total IgG and anti-U1A (RNP) autoantibodies were determined with ELISA.ResultsB cells with a switched “memory-like” (CD19+CD138−IgM−IgD−) (sMB) phenotype were increased in pristane-treated mice and expressed higher levels of Toll like receptor 7 (Tlr7) than cells with this phenotype from untreated mice. Flow-sorted sMB cells from pristane-treated mice did not secrete IgG spontaneously, but were hyper-responsive to both synthetic (R848) and natural (apoptotic cells) TLR7 ligands, resulting in increased IgG production in vitro. The flow-sorted sMB cells also could be driven by R848 to produce IgG anti-U1A autoantibodies. Production of IgG was strongly inhibited by both JSH-23 and SB203580, suggesting that the canonical NFκB and p38 MAPK pathways, respectively, contribute to the TLR7 ligand hyper-responsiveness of sMB from pristane-treated mice.ConclusionsThe switched memory B cell subset from pristane-treated mice is expanded and shows an increased propensity to undergo terminal (plasma cell) differentiation in response to synthetic and natural TLR7 ligands. The data suggest that the decreased clearance of apoptotic cells characteristic of pristane-treated mice might help maintain high serum levels of anti-RNP/Sm autoantibodies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0886-9) contains supplementary material, which is available to authorized users.
Highlights
Pristane-treated mice chronically produce high levels of anti-ribonucleoprotein/Smith and other lupus autoantibodies
To assess the effect of pristane treatment on toll-like receptors (TLR) ligand responsiveness, we cultured positively selected splenic CD19+ B cells (>95 % purity) from pristane-treated and PBS-treated BALB/c mice for 10 days with LPS, R848, or CpG1826 and found that IgG production was stimulated by all three TLR ligands (Fig. 1a)
We hypothesized that apoptotic cells may provide TLR7 ligands that stimulate B cells from pristane-treated mice
Summary
Pristane-treated mice chronically produce high levels of anti-ribonucleoprotein/Smith (anti-Sm/RNP) and other lupus autoantibodies. Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and autoantibody production against nucleic acid-associated proteins, such as anti-Smith/ ribonucleoprotein (anti-Sm/RNP), anti-DNA, and others [1]. Selectivity for these autoantigens may relate to their associated nucleic acids, which are ligands for toll-like receptors (TLR) [2,3,4]. In experimental lupus induced by 2,6,10,14-tetramethylpentadecane (TMPD, pristane), autoantibody production and nephritis are abolished in mice lacking either TLR7 or the IFN-I receptor [7]. TLR7 is IFN-I inducible [8], suggesting that increased TLR7 expression may contribute to B cell hyperactivity and autoantibody production in SLE [9]. TLR7 could be involved in the initial breach of tolerance, the maintenance of serological memory once tolerance has been broken, or
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