Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus.
Patients with systemic lupus erythematosus (SLE) have increased blood levels of IFN-alpha, which correlate to disease activity. We previously identified an IFN-alpha-inducing factor (IIF) in the blood of SLE patients that activated the natural IFN-alpha-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-alpha production in cultures of normal PBMC in the presence of costimulatory IFN-alpha2b. However, they converted the plasmid pcDNA3, which itself induced no IFN-alpha production in PBMC, into an efficient IFN-alpha inducer. A human monoclonal anti-ss/dsDNA Ab had the same effect. This IFN-alpha-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-alpha production in natural IFN-alpha-producing cells, a unique cell population resembling immature dendritic cells. The IFN-alpha production was greatly enhanced by IFN-alpha2b and IFN-beta, 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-alpha induction, that might be important in the pathogenesis of SLE.
Vallin
H
H
Section of Immunology, Department of Veterinary Microbiology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Perers
A
A
Alm
G V
GV
Rönnblom
L
L
D000936:Antigen-Antibody Complex; D001323:Autoantibodies / Q000276:immunology*; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016898:Interferon-alpha / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D010957:Plasmids / Q000276:immunology*
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D016898:Interferon-alpha; D004247:DNA