Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-α) production acting on leucocytes resembling immature dendritic cells

Abstract

Patients with active SLE often have an ongoing production of IFN-alpha. We therefore searched for an endogenous IFN-alpha-inducing factor (IIF) in SLE patients and found that their sera frequently induced production of IFN-alpha in cultures of peripheral blood mononuclear cells (PBMC) from healthy blood donors, especially when the PBMC were costimulated with the cytokines IFN-alpha2b and granulocyte-macrophage colony-stimulating factor (GM-CSF). The phenotype of the IFN-alpha-producing cells (IPC) as determined by flow cytometry corresponded to that of the natural IPC, resembling immature dendritic cells. The IIF activity in SLE sera was sometimes as high as that of a virus and was present especially in patients with active disease and with measurable IFN-alpha levels in serum. The IIF had an apparent molecular weight of 300-1000 kD and appeared to consist of both immunoglobulin and DNA, possibly being immune complexes. This endogenous IFN-alpha inducer may be of pathogenic significance, since a reported occasional adverse effect of IFN-alpha therapy in patients with non-autoimmune disorders is development of anti-dsDNA antibodies and SLE.

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

“…We have previously shown that both SLE IIF and the combination of apoptotic cells and SLE IgG induced IFN␣ production exclusively in the NIPC/PDC population (23,32). We extended these observations in the present study by demonstrating that NIPC/PDCs, enriched on the basis of BDCA-4 expression, produced high levels of IFN␣ in response to material from both apoptotic and necrotic cells, combined with SLE IgG.…”

“…We previously found that the IICs demonstrated in blood contained DNA and not RNA (23), but the present study demonstrates that apoptotic and necrotic cells in vitro also released RNA that was a potent IFN␣ inducer when combined with SLE IgG. One explanation for this apparent discrepancy is that while the RNA released from dying cells in tissues in vivo may be an important IFN␣ inducer at the tissue level, it is then degraded by RNases and therefore not readily detected in the circulation.…”

“…The pronounced concentration dependence of the IFN␣-inducing capacity observed when the apoptotic/necrotic material and SLE IgG were titrated against each other may furthermore indicate that the size of the IC is important. Perhaps only small ICs are active, and this possibility is supported by findings that the SLE IIF in the blood of SLE patients is small (23) and that large ICs prepared by heat aggregation of IgG are inhibitory (53).…”

“…In fact, we previously reported that the elevated serum levels of IFN␣ in SLE are at least partly associated with a circulating endogenous IFN␣ inducer (23). This IFNinducing factor (SLE IIF) consists of small interferogenic ICs (IICs) containing DNA and anti-DNA antibodies, and can be mimicked by combining anti-dsDNA antibodies with the plasmid pcDNA3, provided that the latter contains IFN␣-inducing unmethylated CpG dinucleotides (24).…”

“…Both SLE IIF and the combination of SLE IgG and apoptotic cells selectively induce production of IFN␣ in the natural IFN␣-producing cells (NIPCs) (23,32), which are identical to immature plasmacytoid dendritic cells (PDCs) (33)(34)(35)(36). The NIPC/PDCs are reduced in number in the blood of SLE patients (37,38), but can be demonstrated in increased number in the skin (39,40), probably reflecting a more general recruitment of these cells to tissues in SLE.…”