Fig. 5

Molecular mechanisms of type 1 interferon production in jSLE. A In primary-type 1 interferonopathies, reduced metabolization/removal of cytoplasmic nucleic acid (e.g., through TREX1, SAMHD1, RNASEH2, ADAR1) or increased/spontaneous activation of cytoplasmic nucleic acid sensors (e.g., STING, MDA5) result in increased type 1 IFN expression (IFNA/B) and release. Release of type 1 interferons results in binding to and activation of type 1 IFN receptors (IFNAR), a mechanism that amplifies IFN expression through the Janus Kinase (JAK) signal transducer and activator of transcription (STAT) pathway. B In secondary type 1 interferonopathies but also “classic” SLE, deposition of immune complexes results in their detection by Toll-like receptors (namely TLR3, 7, 9), which triggers type 1 IFN expression and release. Interferons enhance their own expression through the JAK/STAT pathway and cause tissue damage through immune activation and the propagation of inflammation. This results in the release of cellular components and the generation of autoantibodies, which amplifies immune complex formation and deposition. C Type 1 IFN signalling can be inhibited using antiretroviral drugs (e.g., abacavir, lamivudine, zidovudine), IFN-I antibodies (sifalimumab, rontalizumab), or inactivating type 1 IFN receptor antibodies (anifrolumab)