Abstract
Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease pathogenesis. However these mouse studies were confounded by the recent demonstration that the IRF5 knockout mouse line contained a loss-of-function mutation in the dedicator of cytokinesis 2 (DOCK2) gene. As DOCK2 regulates lymphocyte trafficking and Toll-like receptor signaling, this raised the possibility that some of the protective effects attributed to IRF5 deficiency in the mouse lupus models may instead have been due to DOCK2 deficiency. We have therefore here evaluated the effect of IRF5-deficiency in the MRL/lpr mouse lupus model in the absence of the DOCK2 mutation. We find that IRF5-deficient (IRF5−/−) MRL/lpr mice develop much less severe disease than their IRF5-sufficient (IRF5+/+) littermates. Despite markedly lower serum levels of anti-nuclear autoantibodies and reduced total splenocyte and CD4+ T cell numbers, IRF5−/− MRL/lpr mice have similar numbers of all splenic B cell subsets compared to IRF5+/+ MRL/lpr mice, suggesting that IRF5 is not involved in B cell development up to the mature B cell stage. However, IRF5−/− MRL/lpr mice have greatly reduced numbers of spleen plasmablasts and bone marrow plasma cells. Serum levels of B lymphocyte stimulator (BLyS) were markedly elevated in the MRL/lpr mice but no effect of IRF5 on serum BLyS levels was seen. Overall our data demonstrate that IRF5 contributes to disease pathogenesis in the MRL/lpr lupus model and that this is due, at least in part, to the role of IRF5 in plasma cell formation. Our data also suggest that combined therapy targeting both IRF5 and BLyS might be a particularly effective therapeutic approach in lupus.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of tolerance to chromatin and ribonucleoproteins and the deposition of immune complexes in various organs [1]
Lymphoid tissue size and splenic T cell number are reduced in interferon regulatory factor 5 (IRF5)-deficient MRL/lpr mice, whereas the percentage of splenic B cells is increased Lymphadenopathy and splenomegaly are prominent features of murine lupus models and, as expected, this was observed in the IRF5+/+ MRL/lpr mice
As dedicator of cytokinesis 2 (DOCK2) plays an important role in immune function including in TLR signaling, lymphocyte trafficking and the development of Th2-type immune responses it is conceivable that certain effects previously attributed to IRF5 deficiency might instead have been due to the DOCK2 mutation
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of tolerance to chromatin and ribonucleoproteins and the deposition of immune complexes in various organs [1]. The treatment itself may cause appreciable morbidity and responses to treatment are often incomplete. SLE is caused by an incompletely understood interaction between genetic and environmental factors [1]. Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) have been strongly associated with an increased risk of developing lupus in multiple human genetic studies [2,3,4,5]. The polymorphisms contributing to the high-risk IRF5 haplotype are thought to induce novel IRF5 isoforms and/or increase the level of IRF5 expression by increasing the stability of IRF5 protein or mRNA leading to IRF5 gain-of-function [4,6,7,8,9,10,11]
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