Irf5‐deficient mice are protected from pristane‐induced lupus via increased Th2 cytokines and altered IgG class switching

Abstract

Polymorphisms in the transcription factor interferon (IFN ) regulatory factor 5 (IRF 5 ) 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 IRF 5 in SLE development is supported by the fact that increased IRF 5 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 IRF 5 is required for pristane‐induced SLE via its ability to control multiple facets of autoimmunity. We show that IRF 5 is required for pathological hypergammaglobulinemia and, in the absence of IRF 5, I gG class switching is reduced. Examination of in vivo cytokine expression (and autoantibody production) identified an increase in I rf5^−/− mice of T h2 cytokines. In addition, we provide clear evidence that loss of I rf5 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 IRF 5 for autoimmunity and provide a significant new insight into how overexpression of IRF 5 in blood cells of SLE patients may contribute to disease pathogenesis.