Mapping BAFF/APRIL dependency across autoimmune diseases: A mechanistic framework for understanding differential therapeutic responses - PubMed
3 hours ago
- #BAFF/APRIL axis
- #B-cell homeostasis
- #Autoimmune diseases
- B-cell-targeted therapies have improved autoimmune disease outcomes, but non-selective B-cell depletion has limitations like relapse and infection, leading to a shift toward restoring B-cell homeostasis.
- The BAFF/APRIL axis is crucial for B-cell homeostasis, regulating peripheral tolerance, germinal center reactions, and plasma cell survival, with functions varying by context, tissue, and disease stage.
- Therapies targeting the BAFF/APRIL axis show differential responses across diseases, indicating disease diagnosis alone is insufficient to predict outcomes, prompting a mechanistic framework for understanding these variations.
- A BAFF/APRIL dependency map is proposed, using BAFF and APRIL dependence as axes to categorize three mechanistic endotypes: Threshold type, GC/ectopic lymphoid structure type, and long-lived plasma cell niche type.
- This framework aims to guide patient stratification, treatment selection, and trial design by matching each endotype to appropriate drug modalities and expected immunological changes, while including safety guardrails for hypogammaglobulinemia and infection management.
- The review integrates immunology, pharmacology, and clinical evidence, offering a hypothesis-generating tool that requires prospective validation before clinical application.