Anti-Double-Stranded DNA Antibodies and Immunostimulatory Plasmid DNA in Combination Mimic the Endogenous IFN-α Inducer in Systemic Lupus Erythematosus

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Abstract
Patients with systemic lupus erythematosus (SLE) have increased blood levels of IFN-α, which correlate to disease activity. We previously identified an IFN-α-inducing factor (IIF) in the blood of SLE patients that activated the natural IFN-α-producing cells in cultures of normal PBMC. The SLE-IIF contained DNA and IgG, possibly as small immune complexes. In our study, we demonstrated that SLE-IIF correlated to the presence of anti-dsDNA Abs in patients and contained anti-dsDNA Abs as an essential component. Purified anti-DNA Abs or SLE-IgG caused only a weak IFN-α production in cultures of normal PBMC in the presence of costimulatory IFN-α2b. However, they converted the plasmid pcDNA3, which itself induced no IFN-α production in PBMC, into an efficient IFN-α inducer. A human monoclonal anti-ss/dsDNA Ab had the same effect. This IFN-α-inducing activity of the plasmid was abolished by methylation, suggesting that unmethylated CpG DNA motifs were important. Like IIF in SLE serum, the combination of SLE-IgG and pcDNA3 appeared to stimulate IFN-α production in natural IFN-α-producing cells, a unique cell population resembling immature dendritic cells. The IFN-α production was greatly enhanced by IFN-α2b and IFN-β, and for SLE-IIF it was also enhanced by GM-CSF but inhibited by IL-10. We have therefore identified a new function of DNA-anti-DNA Ab complexes, IFN-α induction, that might be important in the pathogenesis of SLE.