Naturally self-reactive B cells are poised to cross the selection barrier into autoimmune germinal centers

SummaryRoughly 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.