Disease relevance of TNFSF13B

• The identification of BCMA as a NF-kappaB-activating receptor for TALL-1 suggests molecular targets for drug development against certain immunodeficient or autoimmune diseases [1].
• We also provide evidence suggesting that the constitutive activation of NF-kappaB and BLyS in NHL-B cells forms a positive feedback loop associated with lymphoma cell survival and proliferation [2].
• Finally, the serum levels of BAFF and APRIL were increased about 5-fold in patients with multiple myeloma (MM) as compared with healthy donors [3].
• In this study, we examined BLYS gene expression, function, and regulation in B-cell non-Hodgkin lymphoma (NHL-B) cells [2].
• Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha [4].
• Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels [5].

High impact information on TNFSF13B

• APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role [6].
• BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients [6].
• Ligand-receptor binding revealed by the TNF family member TALL-1 [7].
• Administration of soluble recombinant BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum immunoglobulin concentrations [8].
• The biological profile of BLyS suggests it is involved in monocyte-driven B cell activation [8].

Chemical compound and disease context of TNFSF13B

• B cell activating factor (BAFF), a ligand belonging to the tumor necrosis factor (TNF) family, plays a critical role in regulating survival and activation of peripheral B cell populations and has been associated with autoimmune disease [9].
• BAFF-binding determinants were identified by shotgun alanine-scanning mutagenesis of the BR3 ECD expressed on phage [10].
• A high BLyS level inversely correlated with a poor median overall survival, presence of constitutional symptoms, and increased levels of lactate dehydrogenase in patients with non-Hodgkin's lymphoma [11].
• We have recently reported the isolation of a human immunodeficiency virus type 1 (HIV-1), KB-1gp32 carrying a shorter size (32 kDa) of transmembrane glycoprotein (TMP) from TALL-1 cells persistently infected with KB-1gp41 virus strain (Shimizu et al., 1990a) [12].
• Effect of dexamethasone of the growth of two T-cell acute lymphoblastic leukemia (T-ALL) cell lines, JM and TALL-1 and an American Burkitt lymphoma cell line, Ramos, of B-cell type was examined [13].

Biological context of TNFSF13B

• BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B cells [14].
• B-lymphocyte stimulator (BLyS) is a TNF family member that is critical for maintenance of normal B-cell development and homeostasis [14].
• The mechanisms involved in BLYS gene expression and regulation are still incompletely understood [2].
• B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have been shown to promote multiple myeloma (MM) cell growth [15].
• B cell-activating factor of the TNF family and a proliferation-inducing ligand cooperate with LMP1 to induce Ig class switching because their neutralization by appropriate soluble decoy receptors attenuates CSR in LMP1-expressing B cells [16].

Anatomical context of TNFSF13B

• TALL-1 is a recently identified member of the tumor necrosis factor (TNF) family that costimulates B lymphocyte proliferation [1].
• APRIL and BAFF were potent survival factors for exogenous cytokine-dependent myeloma cell lines and were autocrine growth factors for the RPMI8226 and L363 autonomously growing cell lines [3].
• NLCs expressed significantly higher levels of APRIL than monocytes and significantly higher levels of BAFF and APRIL than CLL B cells [4].
• Finally, we provide evidence that BLyS is expressed by MM cells and is present in the bone marrow of patients with MM [17].
• In summary, our results suggest that macrophage- and DC-derived B-cell-activating factor belonging to the TNF family (BAFF) represents a key molecule by which macrophages and DCs directly regulate human B-cell proliferative responses to T-cell-independent stimuli [18].

Associations of TNFSF13B with chemical compounds

• BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone [3].
• Second, shotgun alanine scanning of BCMA was used to map critical residues for either APRIL or BAFF binding [19].
• Supernatants of cultures with BAFF and APRIL contained elevated PGE2 [20].
• Of relevance to both protective and pathogenic responses to Ag is the recent finding that soluble molecules of the innate immune system, i.e., IL-4, B cell-activation factor of the TNF family (BAFF), and C3, exhibit significant synergy in promoting the clonal expansion of human B2 cells following low-level BCR ligation [20].
• B lymphocyte stimulator (BLyS) is a member of tumor necrosis factor (TNF) family [21].
• This translated into a survival advantage of 16 days (P < 0.05), a decrease in tartrate-resistant acid phosphatase-positive osteoclasts, and a reduction in radiologically evident lytic lesions in anti-BAFF-treated animals [22].
• These findings indicate that as neutrophils enter the site of inflammation, they release surface-expressed BLyS in a TNFalpha-dependent manner, and thus may contribute to local stimulation of autoimmune B cell responses [23].

Physical interactions of TNFSF13B

• A soluble receptor containing the extracellular domain of BCMA blocks the binding of TALL-1 to its receptor on the plasma membrane and inhibits TALL-1-triggered B lymphocyte costimulation [1].
• Substitution of Tyr13 was tolerated for BAFF binding but not APRIL binding [19].
• Expression of TACI in HEK293T cells confers on the cells the ability to bind BLyS with subnanomolar affinity [24].
• TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation [25].
• The construct rGel/BLyS specifically binds and internalizes through BAFF-R into CD19(+) B-CLL lymphocytes and induces apoptosis at nanomolar concentrations [26].

Regulatory relationships of TNFSF13B

• We show in this study that non-Hodgkin's lymphoma (NHL) B cells express B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two powerful B cell-activating molecules usually expressed by myeloid cells [27].
• Coimmunoprecipitation experiments indicated that BAFF-R interacts with TRAF3 in B lymphoma cells and this interaction is stimulated by TALL-1 treatment [28].
• Significantly, we show that enhancement of BL cell survival by IL-10-activated macrophages is mediated by a BAFF-dependent component and that BAFF is produced at high levels by tumor-associated macrophages in situ [29].
• We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand-related leukocyte-expressed ligand 1 (TALL-1) as a novel member of the TNF ligand family that is functionally involved in B cell proliferation [25].
• Soluble TACI extracellular domain protein specifically blocks TALL-1-mediated B cell proliferation without affecting CD40- or lipopolysaccharide-mediated B cell proliferation in vitro [25].
• We found that IFNgamma-induced BAFF synthesis is inhibited by simultaneous stimulation with either TLR ligands or TNFalpha [30].

Other interactions of TNFSF13B

• Overexpression of BCMA activates NF-kappaB, and this activation is potentiated by TALL-1 [1].
• Altogether, these data suggest that APRIL/BAFF inhibitors may be of clinical value in MM [3].
• Outside of the turn, mutagenesis identifies additional hydrophobic contacts that enhance the BAFF-BR3 interaction [10].
• TACI expression is a good indicator of a BAFF-binding receptor [15].
• Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas [2].

Analytical, diagnostic and therapeutic context of TNFSF13B

• We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM [14].
• Moreover, a soluble form of BAFF was detected using surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry (SELDI-TOF MS) in the sera of B-CLL patients but not of healthy donors [31].
• Transduced CEM cells binding epitope-tagged BlyS protein were identified by flow cytometry [32].
• Coculture of macrophages with BL cells further enhanced BAFF secretion [29].
• The results of competitive ELISA demonstrated that PT could inhibit the binding of BCMA-Fc and anti-BLyS antibody to BLyS in vitro [21].

References