A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors

Nat Commun. 2018 Mar 23;9(1):1199. doi: 10.1038/s41467-018-03323-8.


The 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • B-Cell Activating Factor / chemistry*
  • B-Cell Activating Factor / genetics
  • B-Cell Activating Factor / physiology*
  • B-Cell Activation Factor Receptor / chemistry*
  • B-Lymphocytes / cytology*
  • Cell Differentiation
  • Cell Survival
  • Cross-Linking Reagents / chemistry
  • Female
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fragments / chemistry
  • Lymphopenia / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation
  • Protein Binding
  • Protein Domains
  • Recombinant Fusion Proteins / pharmacology


  • Antibodies, Monoclonal, Humanized
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • Cross-Linking Reagents
  • Immunoglobulin Fragments
  • Recombinant Fusion Proteins
  • TNFRSF13C protein, human
  • TNFSF13B protein, human
  • Tnfrsf13c protein, mouse
  • Tnfsf13b protein, mouse
  • belimumab
  • TACI receptor-IgG Fc fragment fusion protein