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

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Abstract
Objective To investigate the release of interferon‐α (IFNα)–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 IFNα induction was investigated by RNase and DNase treatment. The IFNα levels were measured by immunoassay. Results Both necrotic and apoptotic U937 cells released material that, combined with SLE IgG, induced IFNα production in PDCs. The release from apoptotic cells occurred with a 16‐hour delay, in late apoptosis. Also, normal PBMCs released IFNα‐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 IFNα in PDCs. The IFNα 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 IFNα in SLE and could be of etiopathogenic importance.
Funding Information
  • Swedish Research Council
  • Swedish Society of Medicine
  • Swedish Rheumatism Foundation
  • Uppsala University Hospital Development Foundation
  • King Gustaf V 80-Year Foundation
  • Åke Wiberg Foundation
  • Nanna Svartz Foundation
  • Börje Dahlin Foundation
  • Magnus Bergvall Foundation
  • Brunnberg Foundation