Induction of interferon-a production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late anoptotic cells and lupus IgG

Objective. To investigate the release of interferon-alpha (IFNalpha)-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 IFNa induction was investigated by RNase and DNase treatment. The IFNa levels were measured by immunoassay. Results. Both necrotic and apoptotic U937 cells released material that, combined with SLE IgG, induced IFNa production in PDCs. The release from apoptotic cells occurred with a 16-hour delay, in late apoptosis. Also, normal PBMCs released IFNalpha-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 IFNalpha in PDCs. The IFNa 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 IFNalpha in SLE and could be of etiopathogenic importance.