Targeting type I interferons in systemic lupus erythematous

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with systemic clinical manifestations including, but not limited to, rash, inflammatory arthritis, serositis, glomerulonephritis, and cerebritis. Treatment options for SLE are expanding and the increase in our understanding of the immune pathogenesis is leading to the development of new therapeutics. Autoantibody formation and immune complex formation are important mediators in lupus pathogenesis, but an important role of the type I interferon (IFN) pathway has been identified in SLE patients and mouse models of lupus. These studies have led to the development of therapeutics targeting type I IFN and related pathways for the treatment of certain manifestations of SLE. In the current narrative review, we will discuss the role of type I IFN in SLE pathogenesis and the potential translation of these data into strategies using type I IFN as a biomarker and therapeutic target for patients with SLE.

Keywords: dendritic cell; interferons; lupus (SLE); rheumatology; treatment.

FIGURE 1

Type 1 IFN signaling. Type 1 IFN signaling is mediated through several steps. (McCarty et al., 1995). Activation of endosomal TLR7/9 by viral ssDNA/RNA or endogenous nucleic acids in pDCs leads to IFN-α/β production. Activation of an important receptor, BDCA2, also promotes IFN-α/β production (Izmirly et al., 2017). In the canonical pathway, IFN-α/β binds to the IFN-α receptor (IFNAR) in IFN responsive cells (Izmirly et al., 2021). This leads to phosphorylation and activation of IFNAR associated JAKs (JAK1, Tyk2) (International Consortium for Systemic Lupus Erythematosus et al., 2008). The activated JAKs phosphorylate STAT1/STAT2, which form a heterodimer that further complexes with IRF9 in the cytoplasm (Hom et al., 2008). Finally, the STAT1-STAT2-IRF9 complex translocates to the nucleus, binds to conserved IFN-stimulated response elements (ISREs), and leads to transcription of IFN stimulated genes (ISGs).