Dynamic control of autoreactive B cells from spontaneous germinal centers.

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.