BAFF and BAFF-Receptor in B Cell Selection and Survival

Abstract

The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.

Keywords: B cell; BAFF - B-cell activating factor; BAFF-R; BAFF-R deficiency; NF-k B; TNFRSF13C; primary immumunodeficiencies.

Figure 1

Expression of BAFFR. TACI and BCMA in B cell development. Critical developmental steps depending on BAFF and APRIL-induced signals are shown by the presence of the respective ligand.

Figure 2

BAFFR-induced intracellular signaling. Without BAFF, NIK is complexed to TRAF3 and degraded in the proteasome. BAFF binding to BAFFR recruits TRAF3 to BAFFR and stabilizes NIK while TRAF3 is degraded by the proteasome. NIK activates the non-canonical NF-κB2 signaling pathway and allows nuclear translocation of NF-κB2 p52/relB heterodimers. BAFF binding also activates the PI3K pathway, which shares common components with BCR signaling. The exact mechanisms leading to PI3K activation are still not understood.