Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal production of interferon type I has been widely related to multiple autoimmune diseases, particularly systemic lupus erythematosus (SLE). It has been considered the molecular signature characterized by the overexpression of type I Interferon related genes in SLE patients. Among these, are the interferon regulatory factors (IRF). These transcription factors have been involved in the innate immune response, mainly the one related to the defense against viral infections; the development of immune cells and carcinogenesis. The role of IRF in autoimmune pathology has been addressed in diverse murine models. However, evidence in humans is quite scant. This review will focus on the evidence that supports the role of IRF in the development or susceptibility to autoimmune diseases. Specific emphasis will be made over the role of IRF-5 and IRF-7, since evidence of its association to the development of pathology, particularly systemic lupus erythematosus is the strongest.
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PMID:Interferon regulatory factors: beyond the antiviral response and their link to the development of autoimmune pathology. 2187 84

IRF-5 is a transcription factor activated by toll like receptor (TLR)7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have attenuated IgG2a/c responses to T-cell-dependent and -independent antigens and to polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID mice reconstituted with Irf5-/- B cells show a decrease in IgG2a/c expression after viral infection compared with mice that received wild-type B cells. Irf5-/-B cells in vitro have diminished TLR and cytokine-induced class switching to IgG2a/c. Addressing the molecular mechanism, we show that IRF-5 regulates IgG2a/c expression by decreasing Ikaros expression; reconstitution of IRF-5 in Irf5-/- B cells downregulates Ikaros levels and increases switching to IgG2a/c. The IRF site in ikzf1 promoter binds IRF-5, IRF-4 and IRF-8. We show that IRF-8 but not IRF-4 activates the ikzf1 promoter, and IRF-5 inhibits the transcriptional activity of IRF-8. Collectively, these results identify the IRF-5-Ikaros axis as a critical modulator of IgG2a/c class switching.
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PMID:Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response. 2253