#4-63E. Decoding B Cell Pathways in SLE: Beyond Broad Depletion (Nat Rev Rheumatol, 2026)

As broad B-cell depletion therapies for systemic lupus erythematosus (SLE) show variable efficacy and pose risks to overall protective immunity, how can we develop more precise, targeted treatments? This comprehensive review elucidates the mechanisms by which naive autoreactive B cells in SLE breach tolerance and differentiate through two complementary trajectories: the traditional germinal-centre pathway and the increasingly recognized extrafollicular pathway. Driven by contextual cues such as autoantigen availability and specific T-cell help, both pathways uniquely contribute to the pathogenic autoantibody landscape. A pivotal clinical insight is that the extrafollicular pathway rapidly generates pathogenic, double-negative (DN2) autoantibody-secreting cells independently of typical germinal-centre selection, offering a crucial novel therapeutic target. However, when critically appraising this literature, it is important to note that much of our deep mechanistic understanding still heavily relies on transgenic mouse models, which may not perfectly capture the complex genetic and environmental heterogeneity of human SLE. For practicing rheumatologists, this paradigm shift is highly relevant; it suggests that future interventions will likely move toward precision strategies that selectively modulate these specific pathogenic extrafollicular subsets and their distinct helper T-cells, thereby preserving humoral immunity while effectively controlling flares.

Citation: Zhu, D. Y-D., Castrillon, C., Akama-Garren, E., & Carroll, M. C. Germinal-centre and extrafollicular B cell pathways in systemic lupus erythematosus. Nature Reviews Rheumatology. 2026. DOI: 10.1038/s41584-026-01365-7

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