Functional dichotomy of GC-Derived Memory B Cells in Lupus: A Role for FCRL5+ MBCs in ASC Differentiation 2260895

Abstract Introduction In systemic lupus erythematous (SLE), germinal center (GC)-derived autoreactive memory B cells (MBCs) are a critical reservoir for pathogenic autoantibodies. However, the functional specialization of distinct GC-derived MBC subsets remains poorly defined, creating a major barrier to developing targeted therapies that can selectively deplete pathogenic B cell lineages. Methods We employed a fate-reporter mouse model (S1PR2-tdTomato) within a spontaneous lupus background to precisely track GC-derived B cells. Using this system, we isolated two key MBC subsets, FCRL5+ and CD23+ for functional assessment in vitro and via adoptive transfer. To probe the role of the GC niche, we performed transient ablation of follicular dendritic cells (FDCs) in mixed bone marrow (BM) chimeric animals using the Cxcl13Cre-DTR model. Additionally, we evaluated the therapeutic impact of CD21 blockade on MBC subset dynamics and function. Results We identified a fundamental functional dichotomy. FCRL5+ MBCs demonstrated a superior capacity to differentiate into antibody-secreting cells (ASCs) and produce autoantibodies, while CD23+ MBCs were refractory to ASC differentiation. Depleting FDCs, thereby ablating the GC niche, caused a preferential accumulation of FCRL5+ MBCs and a concurrent loss of the CD23+ subset, demonstrating the GC niche’s essential role in maintaining the CD23+ lineage. Therapeutically, CD21 blockade also ablated GCs and led to the accumulation of a CD21low/- MBC subset with impaired ASC potential. Conclusion Our findings establish a model where FCRL5+ MBCs act as dedicated antibody effectors, while CD23+ MBCs serve as a niche-dependent reservoir for GC re-entry, a process that likely fuels epitope spreading and chronicity. CD21-targeted therapy limits autoimmunity by dismantling the active GC and, crucially, by restricting the supportive niche required for pathogenic, ASC-genic MBC development. Funding Source Department of Defense, Lupus research Alliance (LRA) Topic Categories Therapeutic Approaches to Autoimmunity (THER)