No abstract

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

One remarkable feature of the immune system is its capacity to maintain constant numbers of resting immune cells despite the complex nature of signals needed throughout development and maturation. For many years, B-cell survival was thought to rely solely on B-cell receptor (BCR) tonic signals that would trigger necessary basal survival pathways. The discovery of the tumor necrosis factor (TNF)-like ligand BAFF(B-cell activating factor belonging to the TNF family)/BLyS (B-lymphocyte stimulator) changed these views entirely, as BAFF-deficient mice lack most mature B cells, and treatment with BAFF inhibitors leads to their loss, establishing BAFF as an unappreciated key B-cell survival factor. BAFF-mediated survival signals have been mapped and signaling crosstalk with the BCR has been identified, explaining the need for both BCR- and BAFF-mediated signals for B-cell survival. However, this crosstalk only explains how BCR and BAFF signals cooperate to produce survival proteins and yet, inactivating pro-apoptotic factors such as FOXO proteins, which may be managed separately by BAFF and the BCR, has emerged as an equally important step for survival. In this review, we present new views on B-cell survival, at all stages of B-cell life, and suggest that, in most cases, survival results from the production of appropriate survival factors balanced with the adequate and timely degradation of pro-apoptotic proteins.

Activation-induced cell death (AICD) plays a critical role in immune homeostasis and tolerance. In T-cell-dependent humoral responses, AICD of B cells is initiated by Fas ligand (FasL) on T cells, stimulating the Fas receptor on B cells. In contrast, T-cell-independent B cell responses involve innate-type B lymphocytes, such as marginal zone (MZ) B cells, and little is known about the mechanisms that control AICD during innate B cell responses to Toll-like receptor (TLR) activation. Here, we show that MZ B cells undergo AICD in response to TLR4 activation in vivo. The transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor and TLR4 cooperate to upregulate expression of both FasL and Fas on MZ B cells and also to repress inhibitors of Fas-induced apoptosis signaling. These findings demonstrate an unappreciated role for TACI and its ligands in the regulation of AICD during T-cell-independent B cell responses.