Mapping BAFF/APRIL dependency across autoimmune diseases: A mechanistic framework for understanding differential...

B-cell-targeted therapies have substantially improved outcomes in autoimmune diseases, yet the limitations of non-selective B-cell depletion-including relapse, hypogammaglobulinemia, and infection-have prompted a shift from indiscriminate elimination toward restoring B-cell homeostasis. The BAFF/APRIL axis is central to this homeostatic regulation: it calibrates peripheral tolerance, supports germinal center (GC) reactions, and sustains plasma cell survival niches. Accordingly, its functions are highly context-dependent, varying across tissue microenvironments and disease stages. In practice, therapies targeting this axis have shown clear benefits in some diseases but limited or even harmful effects in others, indicating that disease diagnosis alone cannot reliably predict therapeutic outcomes. This review integrates immunology, pharmacology, and clinical evidence to propose a BAFF/APRIL dependency map. Using BAFF dependence and APRIL dependence as two axes, this hypothesis-generating framework proposes three mechanistic endotypes-Threshold type, GC/ectopic lymphoid structure (ELS) type, and long-lived plasma cell (LLPC) niche type-and matches each to the appropriate drug modality and expected immunological changes. In parallel, we translate safety considerations into practical guardrails: structured monitoring thresholds and management workflows for hypogammaglobulinemia and infection, with principles for combination and sequential therapy. This framework may provide a mechanistic basis for patient stratification, treatment selection hypotheses, and future trial design, but requires prospective validation before being used to inform clinical reasoning.