Naturally self-reactive B cells are poised to cross the selection barrier into autoimmune germinal centers
Year: 2026
Type: article
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 V H 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.
Source: Cell Reports
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
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G157110137, G195907120, G2747453554, Identification and interpretation of introgressed hominin DNA in modern human genomes, Triggering germline-encoded broadly neutralizing antibody responses against influenza virus, G6335432133, G6904567460, G809895527, G9000054876, G9000198365, G9000354948, Sex differences in a cytokine controlling antibody class switch recombination, Evolution of autoreactive GC and epitope spreading in lupus
OpenAlex ID: W7152023071