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Review
. 2012:2012:780436.
doi: 10.1155/2012/780436. Epub 2012 Nov 1.

Interferon regulatory factor 5 in the pathogenesis of systemic lupus erythematosus

Candace M Cham  1 , Kichul Ko, Timothy B Niewold
Affiliations
Review

Interferon regulatory factor 5 in the pathogenesis of systemic lupus erythematosus

Candace M Cham et al. Clin Dev Immunol. 2012.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple genetic risk factors, high levels of interferon alpha (IFN-α), and the production of autoantibodies against components of the cell nucleus. Interferon regulatory factor 5 (IRF5) is a transcription factor which induces the transcription of IFN-α and other cytokines, and genetic variants of IRF5 have been strongly linked to SLE pathogenesis. IRF5 functions downstream of Toll-like receptors and other microbial pattern-recognition receptors, and immune complexes made up of SLE-associated autoantibodies seem to function as a chronic endogenous stimulus to this pathway. In this paper, we discuss the physiologic role of IRF5 in immune defense and the ways in which IRF5 variants may contribute to the pathogenesis of human SLE. Recent data regarding the role of IRF5 in both serologic autoimmunity and the overproduction of IFN-α in human SLE are summarized. These data support a model in which SLE-risk variants of IRF5 participate in a "feed-forward" mechanism, predisposing to SLE-associated autoantibody formation, and subsequently facilitating IFN-α production downstream of Toll-like receptors stimulated by immune complexes composed of these autoantibodies.

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Figures

Figure 1
Figure 1
Schematic model forIRF5 activation. Cells use TLRs as sensors to detect the presence of viruses (V) via TLR7, -8, and -9. Alternatively, apoptotic debris (shown here as membrane blebs, ssRNA, and dsDNA) can also be a source of nuclear proteins and nucleic acids. Nuclear material is brought to the endosome, triggering TLR7, -8, and -9 signaling. Binding of cognate ligands to these TLRs recruits MyD88, a main signaling intermediate involved in TLR7, -8, and -9 signaling. MyD88 recruits interleukin-1 receptor associated kinase (IRAK)-4. IRAK-4 binds and phosphorylates IRAK-1, which in turn recruits Tumor necrosis factor (TNF) receptor associated factor (TRAF) 6 [–48]. TRAF6 is an E3 ubiquitin (Ub) ligase that adds K63-Ub chains to IRF5 [49]. IRF5 is then shuttled to the nucleus and is acetylated by CBP and p300 [50]. Together, these events set the stage for the transcription of IFN-α and other pro-inflammatory cytokine genes.
Figure 2
Figure 2
(a) IRF5 gene marked with previously reported functional variants along with studied SNPs [64]. The first three grey boxes represent differentially spliced first exons (1A, 1B, and 1C), the next light blue boxes represent the exons 2–9, and the last black box indicates the 3′ UTR. SNPs rs2280714 and rs10488631 were used as proxies for rs10954213 in the 3′ UTR due to high LD. (b) IRF5 mRNA isoforms [22]. There are eleven different variants. PEST, proline-, glutamic acid-, serine-, and threonine-rich.
Figure 3
Figure 3
Diagram showing relationships between SLE-associated autoantibodies, IRF5 genotype and IFN-α involved in the pathogenesis of SLE [64]. This suggests a “feed-forward” model in which specific auto-antibodies interact with particular IRF5 risk variants which also predispose to the same antibody formation.
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