Regulation of age-associated B cells by IRF5 in systemic autoimmunity

Nature Immunology
Michela ManniAlessandra B Pernis

Abstract

Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus. Here we found that the lupus syndrome that developed in SWEF-deficient mice was accompanied by the accumulation of ABCs that produced autoantibodies after stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment for motifs bound by transcription factors of the IRF and AP-1 families and the transcription factor T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by the cytokine IL-21 and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated activity of IRF5 in response to stimulation with IL-21. These studies thus elucidate a previously unknown signalin...Continue Reading

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Datasets Mentioned

BETA
GSE99480

Methods Mentioned

BETA
Flow
flow cytometry
RNA-seq
ELISA
ChIP
gene-trapping
FACS
PCR
ELISAs
light microscopy

Software Mentioned

Bioconductor
GSEA
FlowJo TreeStar
ImageJ
UCSC Genome browser
findMotifsGenome
GSEA Hallmark
CLC Bio Genomic Workbench
EDGER
HOMER package

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