Lupus-associated innate receptors drive extrafollicular evolution of autoreactive B cells

In systemic lupus erythematosus, recent findings highlight the extrafollicular (EF) pathway as prominent origin of autoantibody-secreting cells (ASCs). CD21^loCD11c⁺ B cells, associated with aging, infection, and autoimmunity, are contributors to autoreactive EF ASCs but have an obscure developmental trajectory. To study EF kinetics of autoreactive B cell in tissue, we adoptively transferred WT and gene knockout B cell populations into the 564Igi mice - an autoreactive host enriched with autoantigens and T cell help. Time-stamped analyses revealed TLR7 dependence in early escape of peripheral B cell tolerance and establishment of a pre-ASC division program. We propose CD21^lo cells as precursors to EF ASCs due to their elevated TLR7 sensitivity and proliferative nature. Blocking receptor function reversed CD21 loss and reduced effector cell generation, portraying CD21 as a differentiation initiator and a possible target for autoreactive B cell suppression. Repertoire analysis further delineated proto-autoreactive B cell selection and receptor evolution toward self-reactivity. This work elucidates receptor and clonal dynamics in EF development of autoreactive B cells, and establishes modular, native systems to probe mechanisms of autoreactivity.