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Review
. 2015 Feb;165(2):283-95.
doi: 10.1016/j.trsl.2014.10.002. Epub 2014 Oct 13.

Interferon regulatory factors: critical mediators of human lupus

Mark A Jensen  1 , Timothy B Niewold  2
Affiliations
Review

Interferon regulatory factors: critical mediators of human lupus

Mark A Jensen et al. Transl Res. 2015 Feb.

Abstract

The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial, and the interferon regulatory factors (IRFs) play an important role. Autoantibodies formed in SLE target nuclear antigens, and immune complexes formed by these antibodies contain nucleic acid. These immune complexes can activate antiviral pattern recognition receptors (PRRs), resulting in the downstream activation of IRFs, which can induce type I interferon (IFN-I) and other inflammatory mediators. Genetic variations in IRFs have been associated with susceptibility to SLE, and current evidence supports the idea that these polymorphisms are gain of function in humans. Recent studies suggest that these genetic variations contribute to the break in humoral tolerance that allows for nucleic acid binding autoantibodies, and that the same polymorphisms also augment IFN-I production in the presence of these autoantibody immune complexes, forming a feed-forward loop. In this review, we will outline major features of the PRR/IRF systems and describe the role of the IRFs in human SLE pathogenesis.

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Figures

Figure 1
Figure 1
Pattern Recognition Receptor IFN-α Response to Nucleic Acids MDCs/Macrophages and PDCs. In MDCs and macrophages, nucleic acid receptors are detected by RNA and DNA sensing receptors in the cytoplasm and by Toll like receptors (TLR3, TLR7, TLR8, and TLR9) that detect nucleic acids and signal within endolysosomes. The cytosolic DNA sensors, cGAS, DDX41, and IFI16 signal through STING to activate the kinase TBK1 that then phosphorylates IRF3 that then leads to IFN-1 production. cGAS, once activated induces synthesis of cGAMP which binds to and activates STING. The two cytosolic RNA receptors, MDA5 and RIG1, signal through MAVS to activate the kinases TBK1 and IKKε that then phosphorylate IRF3 and IRF7 respectively, and also IRF5 under certain conditions. TLR3, TLR7 and TLR8 sense RNA and TLR9 sensed DNA when imported to endolysosomes by absorptive receptors, such as Fc receptors expressed by dendritic cells and macrophages. TLR3 signals through TRIF and TRAF6 to activate IRF3 while TLR7, TLR8, and TLR9 signal through Myd88 to activate IRF5. PDCs have the capacity to produce large amounts of IFN-α when activated through the TLR7 and TLR9 receptors by signaling through IRF7. TLR triggering in these cells also seems able to activate IRF5 leading to production of IFN-β.
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References

    1. Goldblatt F, O’Neill SG. Clinical aspects of autoimmune rheumatic diseases. Lancet. 2013;382:797–808. - PubMed
    1. Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M. High levels of circulating early apoptic peripheral blood mononuclear cells in systemic lupus erythematosus. Lupus. 1998;7:113–118. - PubMed
    1. Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014;14:166–180. - PMC - PubMed
    1. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994;179:1317–1330. - PMC - PubMed
    1. Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med. 1998;188:2313–2320. - PMC - PubMed

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