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The BLyS family of receptors includes two cytokines, BLyS and APRIL; and three receptors, BR3, BCMA and TACI. Together, these regulate the size and composition of peripheral B cell pools. The multiplicity of ligand-receptor sets, in conjunction with differential receptor expression, alternative binding partners and disparate downstream signaling characteristics, affords the potential to establish independently regulated homeostatic niches among primary and antigen-experienced B cell subsets. Thus, BLyS signaling via BR3 is the dominant homeostatic regulator of primary B cell pools, whereas APRIL interactions with BCMA likely govern memory B cell populations. Short-lived antibody forming cell populations and their proliferating progenitors express a TACI-predominant signature. Further, within each niche, relative fitness to compete for available cytokine is determined by exogenous inputs via adaptive and innate receptor systems, affording intramural hierarchies that determine clonotype composition.

Naïve peripheral B cells survive in vivo because of active stimulation by the TNF superfamily ligand B lymphocyte stimulator (BLyS/BAFF). Although the survival promoting properties of BLyS are well known, the signal pathways and molecular effectors that characterize this stimulation are still being elucidated. In this communication, we discuss the signal cascades that effect BLyS dependent survival and the regulation of BLyS induced signaling. We also examine the role of BLyS as a growth factor and propose that BLyS induced metabolic enhancement optimizes the B cell response to BCR and TLR-dependent signaling.

BAFF is a key factor controlling B cell survival and maturation and its over-expression promotes B cell-mediated autoimmune disorders and participates in the progression of B cell lymphomas. Yet, BAFF and a related ligand APRIL are expressed by T lymphocytes and modulate their functions. BAFF and APRIL promote T cell activation and survival. BAFF over-expression in transgenic (Tg) mice enhances T helper 1 (Thl)-driven delayed-type hypersensitivity (DTH), but inhibits T helper 2 (Th2) cell-mediated allergic airway inflammation in mice. Some of these effects are also dependent on BAFF-induced modification of the B cell compartment. Therefore, direct BAFF/APRIL signalling in T cells and/or T cell modulation in response to a BAFF-modified B cell compartment may play an important role in inflammation and immunomodulation.

B cells require signals from multiple sources for their development from precursor cells, and differentiation into effector cells. BAFF has been identified as a critical regulator of B cell development and differentiation. Defects in the production of BAFF and/or expression of its receptors have been associated with a diverse array of human immunopathologies characterised by perturbed B cell function and behaviour, including autoimmunity, malignancy, and immunodeficiency. This review will discuss the role of BAFF in the pathogenesis of these human immune disorders. It will also highlight relevant differences between the function of BAFF in humans and mice and the impact of this on the therapeutic utility of BAFF antagonists in the treatment of different human diseases.