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.