Evolution of self-reactive B cells: lessons from a lupus model

Systemic lupus erythematosus develops when autoreactive B cells escape tolerance and enter differentiation pathways that sustain pathogenic autoantibody responses. A defining feature of lupus is the evolving autoantibody repertoire, in which initially focused autoreactivity broadens over time through recruitment of additional self-reactive B cell clones as well as continued mutation and selection of B cells engaged in the response. Here, we review insights from the 564Igi lupus model, in which a defined autoreactive B cell clone creates an autoimmune environment that permits a previously tolerant polyclonal wild-type (WT) B cell repertoire to enter the response. Studies using mixed bone marrow chimera and adoptive transfer approaches show that WT-derived B cells can be recruited into established autoreactive niches, participate in germinal center and extrafollicular pathways, and contribute to epitope-spread autoantibody responses. We discuss how studies in the present model have reframed epitope spreading as a dynamic process of self-reactive B cell evolution, in which otherwise restrained B cells are incorporated into an ongoing autoimmune response and shaped by the niches that support their activation, differentiation, persistence, and diversification.