Monoallelic IRF5 deficiency in B cells prevents murine lupus.

Alex Pellerin,Gregory A Viglianti,Ying Tan,Kerstin Nundel,Prachi Shukla,Ian R Rifkin,Kei Yasuda,Yao Xie,Ulf Klein,Vanessa Sandra,Ramon G Bonegio,Barry K Horne Jr,Abraham Cohen-Bucay

doi:10.1172/jci.insight.141395

Abstract

Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model. In contrast, similar reduction of IRF5 expression in macrophages, monocytes, and neutrophils did not reduce disease severity. B cell receptor and TLR7 signaling synergized to promote IRF5 phosphorylation and increase IRF5 protein expression, with these processes being independently regulated. This synergy increased B cell–intrinsic IL-6 and TNF-α production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-α production in vitro and in vivo being substantially lower with loss of 1 allele of IRF5. Mechanistically, TLR7-dependent IRF5 nuclear translocation was reduced in B cells from IRF5-heterozygous mice. In addition, we show in multiple lupus models that IRF5 expression was dynamically regulated in vivo with increased expression in GC B cells compared with non-GC B cells and with further sequential increases during progression to plasmablasts and long-lived plasma cells. Overall, a critical threshold level of IRF5 in B cells was required to promote disease in murine lupus.

Highlights

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production, inflammation, and tissue damage in multiple organs resulting from an overactivation of the immune system through various mechanisms [1, 2]
IFN regulatory factor 5 (IRF5) is expressed in both immune cells and non–bone marrow–derived cells [19], and previous reports have suggested a role for IRF5 in non–bone marrow–derived cells in lupus pathogenesis [30]
We demonstrate that heterozygous deficiency of IRF5 in B cells resulted in a marked reduction in lupus disease manifestations

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production, inflammation, and tissue damage in multiple organs resulting from an overactivation of the immune system through various mechanisms [1, 2]. The exact mechanism of how these polymorphisms in IRF5 lead to an increased risk of developing SLE is incompletely understood, it is thought that they lead to increased levels of IRF5 protein expression and/or functional change [3, 4]. Global homozygous or heterozygous deficiency of IRF5 has conferred protection in many mouse models of lupus [5,6,7,8,9,10]. There is both human and mouse genetic evidence that suggests that IRF5 expression levels contribute to disease pathogenesis.

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Results

Conclusion