How IRF7 promotes autoimmune B cell responses and systemic autoimmunity is unclear. Analysis of spontaneous SLE-prone mice deficient in IRF7 uncovered the IRF7 role in regulating autoimmune germinal center (GC), plasma cell (PC), and autoantibody responses and disease. IRF7, however, was dispensable for foreign antigen–driven GC, PC, and antibody responses. Competitive bone marrow (BM) chimeras highlighted the importance of IRF7 in hematopoietic cells in spontaneous GC and PC differentiation. Single-cell RNAseq of SLE-prone B cells indicated IRF7-mediated B cell differentiation through GC and PC fates. Mechanistic studies revealed that IRF7 promoted B cell differentiation through GC and PC fates by regulating the transcriptome, translation, and metabolism of SLE-prone B cells. Mixed BM chimeras demonstrated a requirement for B cell–intrinsic IRF7 in IgG autoantibody production but not in the regulation of spontaneous GC and PC responses. Altogether, we delineate previously unknown B cell–intrinsic and –extrinsic mechanisms of IRF7-promoted spontaneous GC and PC responses, loss of tolerance, autoantibody production, and SLE development.
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7 July 2025
Article|
May 29 2025
IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints
Adam J. Fike
,
Adam J. Fike
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Kristen N. Bricker
,
Kristen N. Bricker
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing)
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
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Michael V. Gonzalez
,
Michael V. Gonzalez
(Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing - review & editing)
4Center for Cytokine Storm Treatment and Laboratory,
Perelman School of Medicine, University of Pennsylvania
, Philadelphia, PA, USA
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Anju Maharjan
,
Anju Maharjan
(Investigation, Validation, Writing - review & editing)
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
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Tien Bui
,
Tien Bui
(Resources)
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
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Keomonyroth Nuon
,
Keomonyroth Nuon
(Resources)
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
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Scott M. Emrich
,
Scott M. Emrich
(Investigation, Methodology)
3Department of Cellular and Molecular Physiology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Julia L. Weber
,
Julia L. Weber
(Investigation)
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
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Sara A. Luckenbill
,
Sara A. Luckenbill
(Investigation)
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Nicholas M. Choi
,
Nicholas M. Choi
(Investigation)
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Renan Sauteraud
,
Renan Sauteraud
(Formal analysis, Software, Visualization)
5Public Health Science,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Dajiang J. Liu
,
Dajiang J. Liu
(Data curation, Formal analysis, Supervision)
5Public Health Science,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Nancy J. Olsen
,
Nancy J. Olsen
(Resources, Writing - original draft, Writing - review & editing)
6Rheumatology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Roberto Caricchio
,
Roberto Caricchio
(Formal analysis, Investigation, Resources, Validation)
7Rheumatology,
UMass Chan Medical School
, Worcester, MA, USA
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Mohamed Trebak
,
Mohamed Trebak
(Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - review & editing)
3Department of Cellular and Molecular Physiology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
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Sathi Babu Chodisetti
,
Sathi Babu Chodisetti
(Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing)
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
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Ziaur S.M. Rahman
(Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Visualization, Writing - review & editing)
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Correspondence to Ziaur S.M. Rahman: [email protected]
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Adam J. Fike
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Kristen N. Bricker
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Michael V. Gonzalez
Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing - review & editing
4Center for Cytokine Storm Treatment and Laboratory,
Perelman School of Medicine, University of Pennsylvania
, Philadelphia, PA, USA
Anju Maharjan
Investigation, Validation, Writing - review & editing
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Tien Bui
Resources
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Keomonyroth Nuon
Resources
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Scott M. Emrich
Investigation, Methodology
3Department of Cellular and Molecular Physiology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Julia L. Weber
Investigation
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Sara A. Luckenbill
Investigation
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Nicholas M. Choi
Investigation
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Renan Sauteraud
Formal analysis, Software, Visualization
5Public Health Science,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Dajiang J. Liu
Data curation, Formal analysis, Supervision
5Public Health Science,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Nancy J. Olsen
Resources, Writing - original draft, Writing - review & editing
6Rheumatology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Roberto Caricchio
Formal analysis, Investigation, Resources, Validation
7Rheumatology,
UMass Chan Medical School
, Worcester, MA, USA
Mohamed Trebak
Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - review & editing
3Department of Cellular and Molecular Physiology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
Sathi Babu Chodisetti
Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing - review & editing
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Ziaur S.M. Rahman
Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Visualization, Writing - review & editing
1Department of Microbiology and Immunology,
Pennsylvania State University College of Medicine
, Hershey, PA, USA
2Department of Microbiology and Immunology,
Thomas Jefferson University
, Philadelphia, PA, USA
Correspondence to Ziaur S.M. Rahman: [email protected]
Disclosures: The authors declare no competing interests exist.
M. Trebak’s current affiliation is Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
A preprint of this paper was posted in bioRxiv on February 8, 2025.
Received:
October 13 2023
Revision Received:
November 04 2023
Accepted:
May 01 2025
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
National Institutes of Health
- Award Id(s): RO1 AI162971
Funder(s):
PennState College of Medicine
Funder(s):
American Association of Immunology
Funder(s):
National Cancer Institute
- Award Id(s): 5T32CA060395-25
Funder(s):
Lupus Foundation of America
Funder(s):
National Heart Lung and Blood Institute
- Award Id(s): R35 HL150778
Funder(s):
Pennsylvania Department of Health
© 2025 Fike et al.
2025
Fike et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (7): e20231882.
Article history
Received:
October 13 2023
Revision Received:
November 04 2023
Accepted:
May 01 2025
Citation
Adam J. Fike, Kristen N. Bricker, Michael V. Gonzalez, Anju Maharjan, Tien Bui, Keomonyroth Nuon, Scott M. Emrich, Julia L. Weber, Sara A. Luckenbill, Nicholas M. Choi, Renan Sauteraud, Dajiang J. Liu, Nancy J. Olsen, Roberto Caricchio, Mohamed Trebak, Sathi Babu Chodisetti, Ziaur S.M. Rahman; IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints. J Exp Med 7 July 2025; 222 (7): e20231882. doi: https://doi.org/10.1084/jem.20231882
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