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

Abstract

Objective. To investigate the release of interferon-␣ (IFN␣)-inducing material by necrotic or apoptotic cells, its properties, and the necessity of autoantibodies from systemic lupus erythematosus (SLE) patients for the interferogenic activity.Methods. U937 monocytic leukemia cells or peripheral blood mononuclear cells (PBMCs) were rendered necrotic by freeze-thawing or apoptotic by treatment with ultraviolet light. Cell culture supernatants from these cells and IgG from SLE patients (SLE IgG) were added to cultures of normal PBMCs or purified plasmacytoid dendritic cells (PDCs). The importance of nucleic acids for IFN␣ induction was investigated by RNase and DNase treatment. The IFN␣ levels were measured by immunoassay.Results. Both necrotic and apoptotic U937 cells released material that, combined with SLE IgG, induced IFN␣ production in PDCs. The release from apoptotic cells occurred with a 16-hour delay, in late apoptosis. Also, normal PBMCs released IFN␣-inducing material, but only during necrosis. The interferogenic activity of the necrotic material required the presence of RNA, while both RNA and DNA were important in the apoptotic material. In both cases, the presence of SLE IgG was necessary, and its activity correlated with the presence of antibodies to RNA-binding proteins, but not anti-DNA antibodies.Conclusion. Necrotic and late apoptotic cells release material that, combined with SLE IgG, induces production of IFN␣ in PDCs. The IFN␣ inducers probably consist of immune complexes (ICs) containing RNA and possibly DNA as essential interferogenic components. The presence of such interferogenic ICs could explain the ongoing production of IFN␣ in SLE and could be of etiopathogenic importance.

Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus

“…Other than the correlation with titers of anti-dsDNA antibodies, our findings were consistent with the identification of other IFNinduced transcripts and their correlation with disease activity as described by Feng et al (9) and Kirou et al (8). Initial indications of the involvement of Siglec-1 in type I IFN-mediated pathophysiology arose in our global gene expression studies of purified monocytes from SLE patients and were comparable with previous findings in expression profiles generated with PBMCs from patients with SSc (24).…”

“…All SLE patients had active disease, and their mean score on the SLE Disease Activity Index (SLEDAI) (32) was 17 (range [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. SLE patients had a mean C-reactive protein (CRP) level of 5.7 mg/liter, and a mean erythrocyte sedimentation rate (ESR) of 40 mm/hour.…”

“…Interestingly, hydroxychloroquine, which is often used as a first-line treatment, is also believed to act via IFN suppression through stabilization of microsomes and interference with Toll-like receptors (23). Plasmapheresis probably also reduces levels of IFN by removing IFN-inducing circulating immune complexes (24). Moreover, new approaches targeting type I IFN-like antibodies against IFN, soluble IFN receptors, monoclonal antibodies (mAb) against blood dendritic cell antigen 2, and others are under development (3,25).…”

A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti–Jo‐1 or anti–Ro 52/anti–Ro 60 autoantibodies

“…This suggests an endogenous IFN␣ production in patients who have anti-RNA binding autoantibodies, as reported in patients with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (SS) (14,15).…”

“…Although the cause of type I IFN production in myositis is unknown, one interesting mechanism in the context of autoimmune diseases is the well-documented IFN␣-inducing capacity of immune complexes containing antibodies directed against nucleic acids, DNA or RNA, and associated proteins (14,15). This suggests an endogenous IFN␣ production in patients who have anti-RNA binding autoantibodies, as reported in patients with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (SS) (14,15).…”