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Review
. 2011 Jun;157(6):326-31.
doi: 10.1016/j.trsl.2011.01.006. Epub 2011 Feb 8.

Interferon regulatory factors in human lupus pathogenesis

Rafah Salloum  1 , Timothy B Niewold
Affiliations
Review

Interferon regulatory factors in human lupus pathogenesis

Rafah Salloum et al. Transl Res. 2011 Jun.

Abstract

Systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease that results from both genetic predisposition and environmental factors. Many lines of investigation support interferon alpha (IFN-α) as a causal agent in human lupus, and high levels of serum IFN-α are a heritable risk factor for SLE. Interferon regulatory factors (IRFs) are a family of transcription factors involved in host defense, which can induce transcription of IFN-α and other immune response genes after activation. In SLE, circulating immune complexes that contain nucleic acid are prevalent. These complexes are recognized by endosomal Toll-like receptors, resulting in activation of downstream IRF proteins. Genetic variants in the IRF5 and IRF7 genes have been associated with SLE susceptibility, and these same variants are associated with increased serum IFN-α in SLE patients. The increase in serum IFN-α related to IRF5 and 7 genotypes is observed only in patients with particular antibody specificities. This suggests that chronic stimulation of the endosomal Toll-like receptors by autoantibody immune complexes is required for IRF SLE-risk variants to cause elevation of circulating IFN-α and subsequent risk of SLE. Recently, genetic variation in the IRF8 gene has been associated with SLE and multiple sclerosis, and studies support an impact of IRF8 genotype on the IFN-α pathway. In summary, the SLE-associated polymorphisms in the IRF family of proteins seem to be gain-of-function variants, and understanding the impact of these variants on the IFN-α pathway in vivo may guide therapeutic strategies directed at the Toll-like receptor/IRF/IFN-α pathway in SLE.

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Figures

Figure 1
Figure 1
Proposed relationship between SLE immune complexes, endosomal TLRs, and downstream IRF proteins with respect to IFN-α production in SLE patients. A plasmacytoid dendritic cell is shown, as these cells are thought to be the major IFN-α producing cells.
Figure 2
Figure 2
Representation of the interaction between autoantibodies and IRF5 and IRF7 genotype upon serum IFN-α levels in SLE patients. Bars on the graph represent median serum IFN-α levels in a group of SLE patients defined by the labels on the graph. “Risk” refers to subjects who carry IRF5 or IRF7 polymorphisms associated with SLE susceptibility in case-control studies, and “non-risk” refers to subjects who lack these variants.
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