UMMS Affiliation

Department of Medicine, Division of Rheumatology

Publication Date

2021-07-01

Document Type

Article

Disciplines

Immune System Diseases | Immunity | Immunopathology | Rheumatology

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-alpha production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-alpha 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.

Keywords

Autoimmune diseases, Autoimmunity

Rights and Permissions

Copyright © 2021 Pellerin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1172/jci.insight.141395

Source

Pellerin A, Yasuda K, Cohen-Bucay A, Sandra V, Shukla P, Jr BKH, Nündel K, Viglianti GA, Xie Y, Klein U, Tan Y, Bonegio RG, Rifkin IR. Monoallelic IRF5 deficiency in B cells prevents murine lupus. JCI Insight. 2021 Aug 9;6(15):e141395. doi: 10.1172/jci.insight.141395. PMID: 34197340; PMCID: PMC8410043. Link to article on publisher's site

Journal/Book/Conference Title

JCI insight

Related Resources

Link to Article in PubMed

PubMed ID

34197340

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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