Irf5-deficient mice are protected from pristane-induced lupus via increased Th2 cytokines and altered IgG class switching.
Polymorphisms in the transcription factor interferon (IFN) regulatory factor 5 (IRF5) have been identified that show a strong association with an increased risk of developing the autoimmune disease systemic lupus erythematosus (SLE). A potential pathological role for IRF5 in SLE development is supported by the fact that increased IRF5 mRNA and protein are observed in primary blood cells of SLE patients and this correlates with an increased risk of developing the disease. Here, we demonstrate that IRF5 is required for pristane-induced SLE via its ability to control multiple facets of autoimmunity. We show that IRF5 is required for pathological hypergammaglobulinemia and, in the absence of IRF5, IgG class switching is reduced. Examination of in vivo cytokine expression (and autoantibody production) identified an increase in Irf5(-/-)  mice of Th2 cytokines. In addition, we provide clear evidence that loss of Irf5 significantly weakens the in vivo type I IFN signature critical for disease pathogenesis in this model of murine lupus. Together, these findings demonstrate the importance of IRF5 for autoimmunity and provide a significant new insight into how overexpression of IRF5 in blood cells of SLE patients may contribute to disease pathogenesis.
Department of Biochemistry & Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ 07103, USA.
Di
D
Feng
Lisong
L
Yang
Xiaohui
X
Bi
Rivka C
RC
Stone
Priya
P
Patel
Betsy J
BJ
Barnes
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity; D016207:Cytokines / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis*; D050835:Interferon Regulatory Factors / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000517:prevention & control; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D013729:Terpenes / Q000633:toxicity*; D018418:Th2 Cells / Q000276:immunology*
D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D013729:Terpenes; C009042:pristane