B cell activating factor of the TNF family (BAFF, also known as TNFSF13B) is a type II transmembrane protein which forms a constitutive trimer. However, it can be readily cleaved by furin to release as a soluble factor. In soluble form BAFF can persist as a trimer or assemble into a 60mer, consisting of 20 trimers, which maintains receptor binding capabilities and may indeed bind to more than one receptor at a time. BAFF binds to three receptors: transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI, also known as TNFRSF13B), B cell maturation antigen (BCMA, also known as TNFRSF17). and BAFFR also known as TNFRSF13C). All three receptors display the trimeric structure common to TNFR members and contain TNF receptor associated factor (TRAF) binding sites in their cytoplasmic domains but lack death domains. Both BAFFR and TACI are widely expressed on all B cells, with BAFFR levels increasing as the B cells mature. TACI is particularly high on marginal zone (MZ) and B1 B cells in the mouse and CD27+ memory B cells in humans. BCMA expression is restricted to plasma cells (PCs) in the mouse, though in humans it is also expressed on some germinal center (Ref.1 and 2).
BCMA is a 25kDa glycolipid anchored protein. The BCMA gene codes for a nonglycosylated integral membrane type I protein. The N-terminal part of human proteins contains a conserved six-cysteine motif. The six-cysteine motif of BCMA is not the canonical motif of TNFRs (TNF Receptors) but corresponds to a variant motif present in the fourth repeat of the TNFRI molecule. BCMA can activate the transcription factor NF-KappaB (Nuclear Factor-KappaB) through TRAF5 (TNF Receptor-Associated Factor-5), TRAF6 (TNF Receptor-Associated Factor-6), TRAF3 (TNF Receptor-Associated Factor-3), NIK (NF-KappaB Inducing Kinase), and IKK (I-KappaB Kinase) dependent pathway. Engagement of BCMA also activates JNK (Jun N-terminal Kinases), p38 MAPK (Mitogen Activated Protein Kinase) and the transcription factor Elk1. The intracellular domain of TACI associates with TRAFs and activates NF-KappaB, NF-AT (Nuclear Factor of Activated T-Cells) and JNK, thus presumably transducing signals for B-Cell proliferation and survival (Ref3 and 4). BAFFR contains only four cysteine residues in its extracellular or ligand binding domain, making it the smallest CRD (Cysteine-Rich Domain) in the TNF receptor family. The binding of BAFF to BAFFR is primarily responsible for supporting transitional B-Cell maturation and enhancing the survival of mature B-Cells. Increased BAFF-mediated B-Cell survival has also been shown to enhance humoral immune responses. The identification of BCMA as a NF-KappaB-activating receptor for BAFF suggests molecular targets for drug development against certain immunodeficient or autoimmune diseases.Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFFR, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation- inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G (Ref.5).