Recombinant human BAFF/TNFSF13B/BLyS protein - Bioactive cytokine

BAFF background

B-cell activation factor (BAFF), also known as TNFSF13B or BLyS, is a cytokine belonging to the tumor necrosis factor (TNF) superfamily. It is a homotrimeric transmembrane protein that is proteolytically cleaved to produce soluble forms [1]. Together with A proliferation-inducing ligand (APRIL, aka TNFSF13), BAFF plays a prominent role in B cell differentiation, proliferation, survival, and functional responses.

BAFF is mainly produced by hematopoietic cells, including dendritic cells, monocytes, neutrophils, macrophages, T cells, and activated B cells. Recently, non-hematopoietic cells, including astrocytes, osteoclasts, or epithelial cells [1]. 
BAFF binds specifically to BAFF-R (TNFRSF13C) and shares two other receptors with APRIL, namely BCMA (B-cell maturation antigen, TNFRSF17) and TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor, TNFRSF13B) [1]. Expression levels of BAFF-R, TACI, and BCMA vary with the B cell developmental and maturation stages. This dynamic receptor expression also applies to other cell types, including T cells, monocytes, and dendritic cells.

Each receptor signals through specific pathways [2]:

• BAFF-R:
  The best-described signal transduction from BAFF-R is the non-canonical NF-κB (aka NF-κB₂) pathway, which leads to the downstream assembly of NF-κB (p52/RelB) transcription factor [2-4]. BAFF-R signaling also activates PI3-kinases, ERK1/2 MAP kinases, and the IKK2-dependent canonical NF-κB (aka NF-κB₁) pathway, although the mechanisms by which it does so are unclear [3, 4].
• BCMA:
  Upon ligand binding, BCMA recruits TRAF1, TRAF2, and TRAF3, allowing the activation of the canonical NF-κB (aka NF-κB₁) and p38 and JNK MAP kinase pathways. These pathways have been described to lead to the downstream assembly of NF-κB (p50/p65) and Elk-1 transcription factors [4, 5].
• TACI:
  Upon ligand binding, TACI recruits TRAF2, TRAF5, and TRAF6, allowing the activation of the canonical NF-κB (aka NF-κB₁) and JNK MAP kinase pathways. Each pathway leads to the downstream assembly of transcription factors, including NF-κB (p50/p65) and AP1 [4, 6]. 

The BAFF/APRIL axis in B cells

The BAFF/APRIL system has been extensively described in B cells, in which BAFF and APRIL exert complementary functions.

Immature B cells express high levels of BAFF-R. BAFF/BAFF-R signaling contributes to the transition of immature B cells into mature B cells and promotes the expression of survival genes. Upon antigen activation, mature B cells downregulate the expression of BAFF-R and upregulate BCMA and TACI. Immunoglobulin (Ig) isotype class switching and differentiation into plasmablasts is mediated by BAFF/BAFF-R, BAFF/TACI, and APRIL/TACI signaling. Plasmablasts are proliferating cells that produce large amounts of antibodies to sustain the immune response. Eventually, plasmablasts stop proliferating and become long-lived plasma cells/memory B cells. At this stage, BAFF/APRIL signaling through BCMA and TACI is crucial for the survival of memory B cells.

​References:

1. Ullah M.A. & Mackay F., 2023. The BAFF/APRIL system in cancer. Cancers. 15:1791.
2. Balasubramaniam, M. & Mokhtar, A.M.A., 2024. Past and present discovery of the BAFF/APRIL system – A bibliometric study from 1999 to 2023. Cell Signal. 120:111201.
3. Schweighoffer, E., & Tybulewicz, V.L.J., 2018. Signalling for B cell survival. Curr Op Cell Biol. 51:8-14.
4. Schweighoffer, E., & Tybulewicz, V.L.J., 2021. BAFF signaling in health and disease. Curr Op Immunol. 71:124-131.
5. Hatzoglou, A. et al., 2000. TNF receptor family member BCMA (B Cell Maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kB, Elk-1, c-Jun N Terminal Kinase, and p38 Mitogen-Activated Protein Kinase. J Immunol. 165:1322-1330.
6. Xia, X.Z., et al., 2000. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J Exp Med. 192(1):137-143.