Signaling Pathways of Type I and Type III Interferons and Targeted Therapies in Systemic Lupus Erythematosus

Abstract

Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-α antibodies, anti-IFN-α receptor antibodies, and IFN-α-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients.

Neutrophil Extracellular Traps: Signaling Properties and Disease Relevance

“…(IFN-α). Excessive IFN-α can induce autoimmune phenomena, thus precipitating autoimmune diseases [101,102]. In addition, myeloid DCs uploaded with NETs components can induce ANCA and autoimmunity when injected into naive mice, which can be prevented by treatment with DNase I [103].…”

“…ANCA-IgG can further induce the formation of NETs, which in turn promotes plasmacytoid dendritic cells (pDCs) to secrete interferon α (IFN- α ). Excessive IFN- α can induce autoimmune phenomena, thus precipitating autoimmune diseases [ 101 , 102 ]. In addition, myeloid DCs uploaded with NETs components can induce ANCA and autoimmunity when injected into naive mice, which can be prevented by treatment with DNase I [ 103 ].…”

Cutaneous lupus erythematosus: The impact of self‐amplifying innate and adaptive immune responses and future prospects of targeted therapies

“…[52,53] Type I IFNs play a crucial role in LE pathogenesis as they induce the expression of proinflammatory cytokines fuelling the reciprocal revival of innate and adaptive immune pathways. [9,54] Thus, targeting…”

Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus

“…IFN-α binds to IFN-α/β receptor (IFNAR) consisting of the IFNAR-1(α-subunit) and IFNAR-2 (β-subunit) subunits, which belong to the class 2 helical cytokine receptor family (18). The binding of IFN-α to IFNAR phosphorylates and activates JAK1 and TYK2, which phosphorylates different STAT proteins, forming complexes that move to the nucleus, where it stimulates transcription of genes bearing an IFN-response element (ISRE) or gammaactivated sequences (GAS) inducing different immune response; see Figure 3 (18).…”