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

Author

Listed:
  • Michele Vigolo

    (University of Lausanne)

  • Melissa G. Chambers

    (Harvard Medical School)

  • Laure Willen

    (University of Lausanne)

  • Dehlia Chevalley

    (University of Lausanne)

  • Klaus Maskos

    (Proteros Biostructures GmbH)

  • Alfred Lammens

    (Proteros Biostructures GmbH)

  • Aubry Tardivel

    (University of Lausanne)

  • Dolon Das

    (University of Lausanne)

  • Christine Kowalczyk-Quintas

    (University of Lausanne)

  • Sonia Schuepbach-Mallepell

    (University of Lausanne)

  • Cristian R. Smulski

    (University of Lausanne)

  • Mahya Eslami

    (University of Lausanne)

  • Antonius Rolink

    (University of Basel)

  • Edith Hummler

    (University of Lausanne)

  • Eileen Samy

    (EMD Serono Research & Development Institute)

  • Yves Fomekong Nanfack

    (EMD Serono Research & Development Institute)

  • Fabienne Mackay

    (Monash University)

  • Maofu Liao

    (Harvard Medical School)

  • Henry Hess

    (Merck KGaA)

  • Xuliang Jiang

    (EMD Serono Research & Development Institute)

  • Pascal Schneider

    (University of Lausanne)

Abstract

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.

Suggested Citation

  • Michele Vigolo & Melissa G. Chambers & Laure Willen & Dehlia Chevalley & Klaus Maskos & Alfred Lammens & Aubry Tardivel & Dolon Das & Christine Kowalczyk-Quintas & Sonia Schuepbach-Mallepell & Cristia, 2018. "A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03323-8
    DOI: 10.1038/s41467-018-03323-8
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