Abstract Systemic lupus erythematosus is characterized by activation of many self-reactive B cell clones that produce autoantibodies. This can be modeled using mixed bone marrow chimeras, where autoreactive 564Igi B cells initiate autoimmunity that spreads to wild-type (WT) B cells. The mechanisms controlling the inclusion of new B cell clones into spontaneous germinal centers (GCs) remain unclear. Using CRISPR-Cas9, we generated 2 autoreactive B cell receptor knock-in strains, M05 and G55, based on B cell receptors from WT GC B cells in WT:564Igi chimeras. M05 and G55 mice lacked spontaneous GCs and overt autoantibody production, with receptor editing (λ light chain expression) contributing to tolerance. However, autoreactivity was not purged from the B cell compartment since presence of 564Igi clone allowed M05 and G55 B cells to join GCs and produce autoantibodies. These findings reveal that GCs can override peripheral tolerance, recruiting previously silent autoreactive clones and facilitating diversification of autoantibodies.
Oļeiņika et al. (2025) studied this question.