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

Abstract

Summary Polymorphisms in the transcription factor interferon (IFN) regulatory factor 5 (IRF5) have been identified that show strong association with increased risk of developing the autoimmune disease systemic lupus erythematosus (SLE). A potential pathologic role for IRF5 in SLE development is supported by the fact that increased IRF5 mRNA and protein abundance are observed in primary blood cells of SLE patients that correlate with 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 has a distinct influence on pathological hypergammaglobulinemia and provide evidence for its role in regulating IgG1 class switching and antigen specificity. Examination of in vivo cytokine expression (and autoantibody production) identified an imbalance in Irf5−/− mice favoring Th2 polarization. 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 global effect that IRF5 has on autoimmunity and provides significant new insight into how overexpression of IRF5 in blood cells of SLE patients may contribute to disease pathogenesis.

Interferon regulatory factor 5 in human autoimmunity and murine models of autoimmune disease

“…reduction in IgG class-switching in B-cells in the Irf5 -/-mice was also demonstrated upon pristane induction of SLE(69), which correlates with observations that IRF5 also plays a crucial role in B-cell development. Irf5 -/-mice experience attenuated plasma cell maturation, resulting in splenomegaly due to accumulation of immature B-cells in the spleen.…”

IRF5 controls both acute and chronic inflammation

“…Here we show that inhibition of IRF5 activity leads to reduction in neutrophil influx at the sites of acute inflammation. Thus, in addition to the previously suggested and recently confirmed role of IRF5 in balancing the arms of Th1/ Th17 and Th2 adoptive immune responses (15,30,36), IRF5 also plays a direct role in controlling the innate immune responses leading to host tissue damage. These results augment the evidence suggesting that IRF5 blockade might be an effective therapeutic target.…”

IRF5, IRF8, and IRF7 in human pDCs — the good, the bad, and the insignificant?

“…The importance of murine IRF5 in the development of pristane-induced lupus has been confirmed by two recent studies [36,37] using mice that lack the DOCK2 mutation mentioned above. In the absence of IRF5, hypergammaglobulinemia and type I IFN levels are reduced [36] and pristane-induced monocyte trafficking to the peritoneal cavity is impaired [37].…”

“…The importance of murine IRF5 in the development of pristane-induced lupus has been confirmed by two recent studies [36,37] using mice that lack the DOCK2 mutation mentioned above. In the absence of IRF5, hypergammaglobulinemia and type I IFN levels are reduced [36] and pristane-induced monocyte trafficking to the peritoneal cavity is impaired [37].These studies are of high clinical interest, as genetic variants in IRF5 and IRF8 have been found to be associated with increased serum levels of IFN-α in SLE patients and high SLE susceptibility (as reviewed in [38,39]). Furthermore, a study by Stone et al [40] now provides the first direct evidence of altered IRF5 activation in human monocytes of SLE patients.…”