IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints
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.
Authors
- Ziaur S. M. Rahman (ORCID: https://orcid.org/0000-0001-8431-9681)
- Kristen N Bricker (ORCID: https://orcid.org/0000-0001-8963-9780)
- Scott M. Emrich (ORCID: https://orcid.org/0000-0002-4804-7436)
- Adam J. Fike (ORCID: https://orcid.org/0000-0002-7105-6162)
- Nicholas Choi (ORCID: https://orcid.org/0000-0003-4801-4973)
- Julia L. Weber (ORCID: https://orcid.org/0000-0003-1121-0460)
- Renan Sauteraud (ORCID: https://orcid.org/0000-0002-3485-6849)
- Nancy J. Olsen (ORCID: https://orcid.org/0000-0002-6588-3364)
- Dajiang J. Liu (ORCID: https://orcid.org/0000-0001-6553-858X)
- Michael V. Gonzalez (ORCID: https://orcid.org/0000-0001-9741-475X)
- Roberto Caricchio (ORCID: https://orcid.org/0000-0002-1379-1118)
- Mohamed Trebak (ORCID: https://orcid.org/0000-0001-6759-864X)
- Anju Maharjan (ORCID: https://orcid.org/0000-0001-9290-475X)
- Sathi Babu Chodisetti (ORCID: https://orcid.org/0000-0001-7473-9420)
- Sara A. Luckenbill (ORCID: https://orcid.org/0000-0002-8035-2246)
- Tien Bui (ORCID: https://orcid.org/0000-0002-6141-0770)
- Keomonyroth Nuon
Institutions
- Pennsylvania State University (US)
- Thomas Jefferson University (US)
- University of Massachusetts Chan Medical School (US)
- Department of Public Health (MM)
- Transylvania University (US)
- University of Pennsylvania (US)
- Penn State Milton S. Hershey Medical Center (US)
- Jefferson College (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1084/jem.20231882
- Citations
- 4
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- Lupus Foundation of America
- Pennsylvania Department of Health
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Cancer Institute