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Cited by 164Systemic Lupus Erythematosus ResearchT-cell and B-cell ImmunologyGenomics and Chromatin Dynamics

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

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Manni, Michela, Gupta, Sanjay, Ricker, Edd, Chinenov, Yurii, Park, Sung Ho, Shi, Man, Pannellini, Tania, Jessberger, Rolf +2 more·2018·Nature Immunology
DOI 10.1038/s41590-018-0056-8PMC PMC6095139
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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 signaling pathway that controls ABCs in autoimmunity.

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  • ABCs are characterized by distinct gene expression profiles with expression of transcription factors T-BET, IRF5, and ZEB2.

    “ABCs are characterized by their distinct gene expression profiles with the expression of a set a transcription factor including T-BET, IRF5, and ZEB2 [73 -75].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [74]

    The Results sections on distinctive transcriptional programs and chromatin landscape (page unavailable) report a distinctive profile in autoimmune-prone DKO ABCs, Tbx21 expression, and enrichment of T-bet and IRF binding motifs. The paper also identifies IRF5 as a regulator of these ABCs. It does not establish that ABCs generally express all three named factors: Zeb2 appears as a control locus in the Results and ChIP methods, not as evidence of ZEB2 expression in ABCs. (LLM, conf=0.89)

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Authors
Manni, M., Gupta, S., Ricker, E., Chinenov, Y., Park, S. H., Shi, M., Pannellini, T., Jessberger, R., Ivashkiv, L. B., & Pernis, A. B.
Affiliations
  • Hospital for Special Surgery (US)
  • Cornell University (US)
  • Technische Universität Dresden (DE)
Corresponding author
Pernis, Alessandra B.
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2018-02-26
Volume
19
Issue
4
Pages
407-419
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/s41590-018-0056-8
PMC
PMC6095139
OpenAlex
W2791390833
Cited by
164
References
1
Citations by year
2026: 22 · 2025: 24 · 2024: 18 · 2023: 19 · 2022: 20 · 2021: 16 · 2020: 15 · 2019: 21 · 2018: 8
FWCI
13.02
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
Funders
  • National Institutes of Health (1s10od019986-01, 2r01ai046712-26)
  • National Cancer Institute (F31CA196209)
  • National Institute of Allergy and Infectious Diseases (R21AI044938, R01-AI046712, R01AI044938)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR064883, R01AR070146)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
age-associated B cells, IRF5, systemic lupus erythematosus, T-bet, SWAP-70, IL-21, autoantibodies, chromatin landscape, transcriptional dysregulation, autoimmunity, aging
MeSH terms
Animals, DNA-Binding Proteins, Female, Lupus Erythematosus, Systemic, Mice, Inbred C57BL, Nuclear Proteins, Autoimmunity, Minor Histocompatibility Antigens, B-Lymphocyte Subsets, Mice, Knockout, Guanine Nucleotide Exchange Factors, Interferon Regulatory Factors, Mice

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