Editors' ChoiceAutoimmunity

Double safety reins in wayward B cells

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Science Translational Medicine  28 Mar 2018:
Vol. 10, Issue 434, eaat3886
DOI: 10.1126/scitranslmed.aat3886

Abstract

Two regulatory proteins suppress IRF5 transcription factor in age-associated B cells to prevent systemic autoimmune disorders.

The complexity of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), is underscored by the fact that it took several decades for the U.S. Food and Drug Administration to approve a new medicine, a B cell–targeting monoclonal antibody belimumab, for SLE in 2011. Age-associated B cells (ABCs) are a distinctive CD11c+T-bet+ B cell population that preferentially emerges in older females. They expand in patients with systemic autoimmunity and produce autoantibodies. Yet, it is unclear what controls ABC accumulation. Moreover, although interferon regulatory factor (IRF)5 was identified as one of the gene loci most strongly associated with SLE, how IRF5 activity is modulated remains incompletely understood.

Manni et al. found that ABCs spontaneously expand in female mice lacking switch-associated protein 70 (SWAP70) and differentially expressed in FDCP 6 homolog (DEF6) (two Rho GTPase-regulatory proteins with immunomodulatory functions) but not in those lacking only one of them. Double knockout (DKO) mice lacking both proteins develop lupus-like symptoms associated with increased germinal center B cells and plasma cells. Development of ABCs is driven by interleukin-21 (IL-21), a cytokine produced by helper T cells that interact with B cells. Using next-generation sequencing and sophisticated bioinformatics approaches, the authors identified ABC-specific transcriptionally accessible loci that include many genes involved in cell locomotion and adhesion. Additionally, the chromatin of DKO ABCs displayed more binding of IRF transcription factors. Consistent with these findings, biochemical analysis showed that IL-21 induces IRF5 binding to these ABC-specific gene loci, and both SWAP70 and DEF6 interfere with this process. Notably, deletion of a single copy of Irf5 substantially reduced ABC accumulation and ameliorated the inflammatory diseases in DKO mice, demonstrating that ABC expansion is sensitive to the expression of IRF5.

This study reveals a new signaling axis that restrains ABC formation and inflammation in a murine lupus model. It provides a much-needed fresh insight into the molecular safeguards against systemic autoimmunity, which is particularly important because the DEF6 locus is a genetic risk factor for human SLE. Future studies are warranted to explore whether a similar mechanism operates in human systemic autoimmunity and whether it is malleable for therapeutic intervention.

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