The BAFF/APRIL system at the crossroads of B cell memory and autoimmune relapse: Implication into the therapeutic strategies.

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) exert their functions by engaging distinct receptors, B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI), and BAFF receptor (BAFFR), thereby regulating the differentiation and survival of specific B cell subsets. Humoral immune memory relies on two complementary reservoirs, long-lived plasma cells (LLPCs) and memory B cells (MBCs). They can be categorized from a developmental perspective into low-affinity, short-lived cells generated in a germinal center (GC)-independent manner, and high-affinity, long-lived cells that require GC reactions. As a key survival factor for B cells, the BAFF/APRIL system plays a critical regulatory role in maintaining these compartments. The memory reservoirs particularly in autoimmune disorders where B cells act as central pathogenic drivers, sustain autoreactive antibody pools and largely contribute to disease relapse. Following the success of BAFF/APRIL system targeted biologics, such as belimumab and telitacicept, and with BCMA-directed chimeric antigen receptor T (CAR-T) cell therapy recently showing remarkable efficacy in autoimmune diseases, novel treatment avenues have emerged for cases resistant to conventional B cell depletion strategies. We now recognize that while conventional B cell depletion effectively reduces the circulating B cells to achieve rapid disease control, therapeutic targeting of the BAFF/APRIL system addresses the survival of long-lived subsets such as LLPCs, thereby filling the gap left by depletion strategies and partially contributes to sustained immunological control. These distinctions highlight the rationale for sequential therapeutic strategies, reinforcing the translational potential of precision medicine in autoimmune disease management.