| Title: | Naturally self-reactive B cells are poised to cross the selection barrier into autoimmune germinal centers |
| Journal: | Cell Reports |
| Published: | 8 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41961592/ |
| DOI: | https://doi.org/10.1016/j.celrep.2026.117224 |
Publication 18057
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Abstract
Roughly 20% of circulating B cells react with self-antigens. An open question is whether germline autoreactivities expand when immune tolerance is breached. To test this, we supplied the 564Igi mouse model of spontaneous autoreactive germinal centers (GCs) with naive B cells that were polyclonal with human-like CDRH3 diversity but were genetically constrained to one of two alleles of the human antibody VH gene IGHV1-69. This polymorphism is skewed across global ethnicities, encoding either F54 or L54 in the CDRH2 loop, with L54 endowing autoreactive B cell receptors (BCRs). L54 B cells were selectively retained within 564Igi mice, leading to their incorporation into autoimmune GCs. This advantage was lost within wild-type C57Bl/6. We also demonstrate human-like L54 IGHV1-69 usage within the geographic variation of ancestral Neanderthals and Denisovans. Collectively, our results suggest that the self-reactive B cell pool is ancestral and is positioned for expansion by autoimmune environments.</p>
17 Authors
- Danni Yi-Dan Zhu
- Maya Sangesland
- Vintus Okonkwo
- Zhenrui Zhang
- Victoria Rosado
- Larance Ronsard
- Caitlin McCarthy
- Caroline Alexander
- Ralston M Barnes
- Daniel Rohrer
- Nils Lonberg
- Debashree Tagore
- Musie Ghebremichael
- Carlos Castrillon
- Joshua M Akey
- Michael C Carroll
- Daniel Lingwood
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