The biology of B cell development and activation is rapidly becoming more clear with the characterization of novel ligands and receptors belonging to the TNF superfamily (TNFSF).1 The ligands, BAFF (B cell activating factor)2,3,4 and APRIL5 (a proliferation inducing ligand), are type II membrane proteins that can be released by proteolytic cleavage to form active, soluble homotrimers. BAFF and APRIL are expressed by T cells, dendritic cells, monocytes, and macrophages but not by B cells.2,3 The TNFSF receptors (TNFSFR) that bind BAFF and APRIL, BCMA (B cell maturation antigen)6 and TACI (TNFR homolog transmembrane activator and Ca2+ modulator and CAML interactor),7 are type I membrane proteins with extracellular regions consisting of a characteristic repeated domain structure of approximately 40 amino acids each.8,9 These receptors are expressed almost exclusively by immune cells in the B cell lineage.4,7,10,11 Expression is weak on immature bone marrow B cells but becomes progressively stronger during peripheral B cell development.9 The expression of a third unnamed receptor that binds APRIL but not BAFF has been detected on non-lymphoid cell lines.12
Either BAFF or APRIL can bind either BCMA or TACI at physiological concentration, with Kd values ranging from 160 pM to 1.25 nM.7,9,13-16 These interactions are selective in that BCMA and TACI do not bind other ligands in the TNFSF, and BAFF and APRIL do not bind other TNFSFR family members.10,14-16 Signal transduction within this system typically involves activation of NF-kappa B, caspases, JNK, and ERK.17 These events are induced by BAFF binding, whereas APRIL does not activate NF-kappa B or JNK.5,15 Neither BCMA nor TACI contains a death domain or a recognizable TRAF interacting domain, the presence or absence of which is used to classify TNFSFR members.6,17
In vitro, BAFF or APRIL binding to BCMA or TACI promotes the differentiation and proliferation of B cells.3,4,13,16,18 Both ligands serve as potent coactivators to augment immunoglobulin (Ig) production and to upregulate surface expression of B cell effector molecules.4,14,15,18,19 Consistent with BCMA and TACI expression patterns, both naive B cells and germinal center committed cells respond to the ligands. The bioactivity of BAFF and APRIL as soluble homotrimers distinguishes them from other TNFSF ligands such as TRAIL, FasL, and CD40L, which are only active as membrane bound molecules.13,17
Transgenic mice over-expressing BAFF highlight the involvement of this molecule in immune system function.9,19,20 These mice exhibit increased numbers of peripheral B220+ B cells with a normal proliferation rate. These cells have high levels of Bcl-2 and exhibit prolonged survival and hyperactivity. Serum IgM and IgG titers are elevated in the mice, and the spleens, lymph nodes, and Peyer's patches are enlarged. The number of local effector T cells is also increased. These mice display a lupus-like autoimmune phenotype characterized by high levels of rheumatoid factors, circulating immune complexes, the presence of anti-DNA autoantibodies, and Ig deposition in the kidneys. BAFF appears to be integral to the development and maturation of peripheral B cells in vivo. APRIL injected intraperitoneally in mice also promotes accumulation of splenic B cells, resulting in high spleen weight.13
Over-expression of BAFF has been proposed to underlie the development of autoimmunity by promoting the survival of an immature splenic B cell subset termed transitional type 2 cells.18 Excessive levels of BAFF could alter the homeostasis of immature B cell development and facilitate the continued existence of autoreactive clones that normally would not survive in the spleen. This is observed to be the case in the transgenic mice over-expressing BAFF.20 Soluble BCMA/Fc or TACI/Fc fusion proteins administered to these mice reduce the severity of autoimmune symptoms.9 Other BAFF antagonists also would be expected to interfere with this pathology and would make interesting candidates as human therapeutics directed toward B cell mediated autoimmune diseases.
Studies focused on the third APRIL receptor have raised the possibility of its involvement in tumorigenesis. Several epithelial cell lines can proliferate more rapidly in response to APRIL, even though they do not express BCMA or TACI.12 This observation was extended with a subcutaneous tumor model of HT29 and A459 cell lines in which tumor growth was significantly reduced and nearly prevented by administration of soluble BCMA/Fc fusion proteins.10
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