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.
Highlights
The systemic lupus erythematosus (SLE) is characterized by a wide array of immune tolerance breakdown with systemic inflammation involving the dysregulation of immune responses
The secreted IFNs ligate to the type I or type III IFN receptors (IFN-α/β receptor (IFNAR)1/IFNAR2 or IFN-λ receptor (IFNLR)1/interleukin-10 receptor (IL-10R)2, respectively) of the neighboring cells and stimulate the production of IFN-stimulated genes (ISGs) via Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, which results in the production of several antiviral effectors
Despite the difference in the structures of type I and type III IFN receptors, the engagement of IFN-λs with type III IFN receptors activates the JAK-STAT signaling cascade, recruits interferon regulatory factor (IRF)-9, and activates IFN-stimulated gene factor 3 (ISGF3), which drives the transcription of ISGs; this is similar to the engagement of type I IFNs to their cognate type I IFN receptor
Summary
The systemic lupus erythematosus (SLE) is characterized by a wide array of immune tolerance breakdown with systemic inflammation involving the dysregulation of immune responses. More than 90 risk loci have been identified and have collectively been used to establish several critical pathways involved in SLE pathogenesis, including innate immune responses, lymphocyte activation, and immune complex clearing [6]. These pathways result from the inadequate clearance of nuclear debris and immune complexes, the dysregulation of the innate immune system driven by innate receptors, such as Toll-like receptors (TLRs) and interferon (IFN) signaling, and aberrant immune responses of the adaptive immune system mediated by B-cell and T-cell signals [7]. We discussed current therapies, which target the signaling pathways of type I and type III IFNs, and their results in large-scale clinical trials in SLE
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