BAFF and APRIL Receptors in B Cell Immunity and Autoimmunity

BAFF and APRIL are TNF superfamily proteins that bind to BAFFR, TACI and BCMA, members of the TNF receptor superfamily. These proteins have both unique and overlapping roles in B cell development and survival and are major therapeutic targets for antibody- and B-cell-driven pathologies. BAFF and BAFFR are required for development and survival of follicular and marginal zone (MZ) B cells, whereas BAFF and APRIL acting through TACI and BCMA support plasma cell survival. TACI and BCMA can both be cleaved to generate soluble decoy receptors binding to BAFF or APRIL, forming feedback circuits. Thus, loss of TACI leads to an increase in BAFF, resulting in B cell hyperplasia. Recent work showed that TACI is required for MZ B cell development, a finding that has implications for understanding immune dysfunction in humans. Both monoallelic and biallelic loss-of-function TACI mutations result in immunodeficiency, potentially due to impaired MZ B cell function. Paradoxically, monoallelic TACI mutations predispose to autoimmunity. We propose this may be due to increased BAFF levels which promote selection of self-reactive B cell clones into the mature B cell pool, particularly the MZ B cell compartment. A deeper understanding of this ligand-receptor system is essential for effective therapeutic targeting.