Cracking the BAFF code

Studies showing how BAFF and its closely related homologue APRIL activate their receptors and transmit growth and survival signals to B cells have shed new light on the association between BAFF and autoimmunity. This knowledge has prompted several clinical trials testing BAFF and APRIL antagonists for the treatment of autoimmune diseases and lymphomas. The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting.