Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases

Figures & data

Figure 1. BAFF and APRIL receptor interactions. BAFF and APRIL are first synthetized as type II transmembrane proteins that are mainly expressed in cells of myeloid origin or stromal cells. They are processed to trimeric soluble cytokines by furin or furin-like protease(s). APRIL and BAFF can also assemble as heteromers containing two APRIL and one BAFF, or two BAFF and one APRIL protomers. The three receptors are type III transmembrane proteins (lacking signal peptides) mainly expressed by B cells at different stages of differentiation and whose main, but not exclusive function, is to provide survival and fitness signals to cells. BAFF-R binds BAFF only, and to a lesser extent BAFF-rich but not APRIL-rich heteromer. BAFF–BAFF-R interactions have a dominant role for the maintenance of the peripheral mature naïve B cell pool. TACI binds to both BAFF and APRIL but responds better, if not exclusively, to oligomeric ligands (i.e. containing more than one trimer: membrane-bound BAFF, BAFF 60-mer [containing 20 trimers] or heparan sulphate proteoglycan (HSPG)-bound APRIL). BCMA binds to APRIL with higher affinity than to BAFF. TACI can be cleaved by the ADAM10 metalloprotease to act as a soluble decoy receptor that inhibits both BAFF and APRIL. BCMA can be processed by γ-secretase, releasing a soluble decoy receptor that, in its monomeric form and because of its weak affinity for BAFF, inhibits APRIL only.