TY - JOUR
T1 - Interferon regulatory factors in human lupus pathogenesis
AU - Salloum, Rafah
AU - Niewold, Timothy B.
N1 - Funding Information:
Supported by NIH/NIAID K08 Award AI083790, NIH P30 DK42086, NIAID Clinical Research Loan Repayment AI071651, CTSA Collaborative Pilot Grant from UL1 RR024999, Arthritis National Research Foundation Eng Tan Scholar Award, and grants from the France-Chicago Center, the Alliance for Lupus Research, and the Lupus Research Institute .
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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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U2 - 10.1016/j.trsl.2011.01.006
DO - 10.1016/j.trsl.2011.01.006
M3 - Review article
C2 - 21575916
AN - SCOPUS:79956141306
SN - 1931-5244
VL - 157
SP - 326
EP - 331
JO - Translational Research
JF - Translational Research
IS - 6
ER -