Interferon regulatory factors in human lupus pathogenesis

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-alpha) as a causal agent in human lupus, and high levels of serum IFN-alpha 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-alpha 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-alpha in SLE patients. The increase in serum IFN-alpha 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-alpha 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-alpha 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-alpha pathway in vivo may guide therapeutic strategies directed at the Toll-like receptor/IRF/IFN-alpha pathway in SLE. (Translational Research 2011;157:326-331)