Vigolo, MicheleChambers, MelissaWillen, LaureChevalley, DehliaMaskos, KlausLammens, AlfredTardivel, AubryDas, DolonKowalczyk-Quintas, ChristineSchuepbach-Mallepell, SoniaSmulski, Cristian R.Eslami, MahyaRolink, AntoniusHummler, EdithSamy, EileenFomekong Nanfack, YvesMackay, FabienneLiao, MaofuHess, HenryJiang, XuliangSchneider, Pascal2018-04-192018Vigolo, M., M. G. Chambers, L. Willen, D. Chevalley, K. Maskos, A. Lammens, A. Tardivel, et al. 2018. “A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors.” Nature Communications 9 (1): 1199. doi:10.1038/s41467-018-03323-8. http://dx.doi.org/10.1038/s41467-018-03323-8.http://nrs.harvard.edu/urn-3:HUL.InstRepos:35982084The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes. Binding and activation of BAFFR can therefore be targeted independently to inhibit or activate the function of BAFF. Moreover, structural analyses suggest that the flap of BAFF 60-mer temporarily prevents binding of an anti-BAFF antibody (belimumab) but not of a decoy receptor (atacicept). The observed differences in profiles of BAFF inhibition may confer distinct biological and clinical efficacies to these therapeutically relevant inhibitors.en-USJournal Article2018-04-1910.1038/s41467-018-03323-8