Naturally self-reactive B cells are poised to cross the selection barrier into autoimmune germinal centers
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.
Authors
- Larance Ronsard (ORCID: https://orcid.org/0000-0002-5307-1940)
- Maya Sangesland (ORCID: https://orcid.org/0000-0001-8316-039X)
- Daniel Lingwood (ORCID: https://orcid.org/0000-0001-5631-9238)
- Daniel Rohrer (ORCID: https://orcid.org/0000-0003-2013-6370)
- Musie Ghebremichael (ORCID: https://orcid.org/0000-0002-8572-1944)
- Carlos Castrillón (ORCID: https://orcid.org/0000-0003-2909-7371)
- Vintus Okonkwo (ORCID: https://orcid.org/0000-0002-7812-384X)
- Victoria Rosado (ORCID: https://orcid.org/0000-0003-4187-7418)
- Ralston M. Barnes
- Zhenrui Zhang (ORCID: https://orcid.org/0000-0003-0563-9148)
- Debashree Tagore (ORCID: https://orcid.org/0000-0003-4018-2796)
- Nils Lönberg (ORCID: https://orcid.org/0000-0003-2011-6134)
- Joshua M. Akey (ORCID: https://orcid.org/0000-0002-4411-1330)
- Caitlin McCarthy
- Danni Yi-Dan Zhu
- Michael C. Carroll
- Caroline Alexander
Institutions
- Boston Children's Hospital (US)
- Emory University (US)
- Princeton University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Massachusetts General Hospital (US)
- Bristol-Myers Squibb (United States) (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2026.117224
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Lupus Research Alliance
- National Institutes of Health
- Canadian Institutes of Health Research