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BAFF (BLyS / TALL1)

BAFF /APRIL functions

BAFF (B cell activation factor of the TNF family, also known as BLyS or TALL1) is a cytokine expressed predominantly by cells of the immune system such as neutrophils, monocytes, macrophages, dendritic cells, follicular dendritic cells, activated T cells and some malignant B cells. Interferon-g stimulates the expression of BAFF by these cells. BAFF is a master regulator of peripheral B cell survival, and also acts in processes such as immunoglobulin isotype switch and B cell co-stimulation. Beside its major role in B cell biology, BAFF co-stimulates activated T cells. BAFF is found either at the cell membrane as a type II transmembrane protein or it is released in a soluble form after cleavage by furin-type convertases.[1]. Membrane-bound and soluble BAFF bind to CD19+ B cells, including both naive and memory B cells.

APRIL (A Proliferation-inducing ligand; TRDL-1) is a secreted protein related to BAFF and shares some of the BAFF receptors. APRIL is expressed in monocytes, dendritic cells and T cells. In contrast to BAFF, APRIL is also expressed in several tumor tissues or cell lines, such as colon carcinoma[2].

BAFF and APRIL both bind to TACI (transmembrane activator and calcium-modulator and cyclophilin ligand-interactor) and BCMA (B cell maturation antigen). BAFF, but not APRIL also signals through BAFF Receptor (BAFF-R, BR3). All three receptors are expressed during B cell differentiation, although activated T cells also express BAFF-R. A new third “receptor” for APRIL has been reported: the glycosaminoglycans side chains of proteoglycans are an APRIL-specific binding partner (Figure 1). April binding to the proteoglycans has been postulated to be a prerequisite for APRIL activation by inducing APRIL oligomerization[3, 4].

BAFF and diseases

Interactions of BAFF (B cell activating factor) with BAFF-R, one of three BAFF-binding receptors that are preferentially expressed on B cells, are essential for B cell development. Defects in either the ligand or the receptor arrest progression from immature type-1 B cells to type-2 B cells and mature B cells; B1 B cells are unaffected. Deregulated expression of BAFF leads to autoimmune disorders in mice. Mouse models of lupus-nephritis have been shown to exhibit increased serum BAFF levels correlating with disease severity. In the human, elevated levels of soluble BAFF have been detected in the serum of patients with various autoimmune diseases, such as rheumatoid arthritis (RA), Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) and in patients with tumors, such as multiple myeloma (MM) non-Hodgkin lymphoma (NHL), including B-cell chronic lymphocytic leukemia (B-CLL)[5]. Modulating the level and activity of BAFF in these patients may alleviate symptoms associated with their disease. Several potential therapeutic inhibitors targeting BAFF are under investigation, including an anti-BAFF antibody and receptor-Fc fusion proteins.

Mutations in the BAFF-R and TACI are associated with Common Variable Immunodeficiency (CVID) in humans[6, 7].

Figure 1: Functions of BAFF and APRIL and its receptors in the immune system. BAFF and APRIL interactions with their receptors and functional outcomes of BAFF and /or APRIL signaling are shown.

BAFF, Soluble (human) Detection Set (APO-54N-022)

Summary of features

	For the quantitative determination of soluble human BAFF from biological fluids (serum and cell culture supernatant)
	Monoclonal antibodies-based sandwich ELISA
	Detection limit: 0.3 ng / ml
	Range: 0-30 ng / ml
	Specificity : Detects only human BAFF
	Format: sufficient materials to run ELISAs on 5 x 96-well plates

Principle of the Kit

This assay is a sandwich Enzyme Linked-Immuno-Sorbent Assay (ELISA) developed for the direct measurement of human BAFF (hBAFF) in serum and cell culture supernatants. A monoclonal antibody specific for hBAFF (COAT) is coated onto the wells of the microtiter plate. Samples and concentration standards of hBAFF are pipetted into the wells for binding to the coated antibody. After extensive washing to remove unbound compounds, hBAFF is recognized by the addition of a second monoclonal antibody (DET) specific for hBAFF. After removal of excess antibody, a goat anti-rat IgG (Fcgamma fragment specific) conjugated to horseradish peroxidase (HRP) is added. Following a final washing, peroxidase activity is quantified using the substrate 3,3’,5,5’-tetramethylbenzidine (TMB). The intensity of the color reaction is measured at 450 nm after acidification and is directly proportional to the concentration of hBAFF in the samples.

Figure 2: Linearity of the STD curve.

LITERATURE OVERVIEW:

[1] Schneider, P. (2005). The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol 17, 282-289.

[2] Rennert, P., Schneider, P., Cachero, T.G., Thompson, J., Trabach, L., Hertig, S., Holler, N., Qian, F., Mullen, C., Strauch, K., Browning, J.L., Ambrose, C., and Tschopp, J. (2000). A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth. J Exp Med 192, 1677-1684.

[3] Ingold, K., Zumsteg, A., Tardivel, A., Huard, B., Steiner, Q.G., Cachero, T.G., Qiang, F., Gorelik, L., Kalled, S.L., Acha-Orbea, H., Rennert, P.D., Tschopp, J., and Schneider, P. (2005). Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med 201, 1375-1383.

[4] Hendriks, J., Planelles, L., de Jong-Odding, J., Hardenberg, G., Pals, S.T., Hahne, M., Spaargaren, M., and Medema, J.P. (2005). Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation. Cell Death Differ 12, 637-648.

[5] Mackay, F., and Tangye, S.G. (2004). The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers. Curr Opin Pharmacol 4, 347-354.

[6] Salzer, U., Chapel, H.M., Webster, A.D., Pan-Hammarstrom, Q., Schmitt-Graeff, A., Schlesier, M., Peter, H.H., Rockstroh, J.K., Schneider, P., Schaffer, A.A., Hammarstrom, L., and Grimbacher, B. (2005). Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37, 820-828.

[7] Losi, C.G., Silini, A., Fiorini, C., Soresina, A., Meini, A., Ferrari, S., Notarangelo, L.D., Lougaris, V., and Plebani, A. (2005). Mutational Analysis of Human BAFF Receptor TNFRSF13C (BAFF-R) in Patients with Common Variable Immunodeficiency. J Clin Immunol 25, 496-502.