Review Article | Published:

The BAFF/APRIL system in SLE pathogenesis

Nature Reviews Rheumatology volume 10, pages 365373 (2014) | Download Citation

Abstract

Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic monoclonal antibody that neutralizes the cytokine TNF ligand superfamily member 13B (also known as B-cell-activating factor of the TNF family [BAFF]), belimumab, became the first targeted therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF therapies. The role of a related cytokine, TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) in SLE is much less well understood, and hence this review focuses on BAFF.

Key points

  • TNF ligand superfamily member 13B (also known as B cell-activating factor of the TNF family [BAFF]) and TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) are important modulators of autoimmunity

  • Data indicate that alteration of the BAFF/APRIL system affects the capacity of the innate immune system to regulate B-cell activation

  • BAFF and type I interferons function together in systemic lupus erythematosus (SLE) pathogenesis in both a Toll-like receptor-dependent and independent manner

  • Defining the clinical manifestations of disease related to alterations of the BAFF/APRIL system might help to stratify patients with SLE into subgroups that are more likely to benefit from anti-BAFF treatment

  • Differences in the molecular forms of BAFF might affect the efficacy of BAFF-specific therapies

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Affiliations

  1. Department of Immunology, Monash University, Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Vic 3004, Australia.

    • Fabien B. Vincent
    •  & Fabienne Mackay
  2. Monash University Centre for Inflammatory Diseases, Southern Clinical School, Monash Medical Centre, 246 Clayton Road, Clayton, Vic 3168, Australia.

    • Eric F. Morand
  3. Department of Biochemistry, University of Lausanne, Boveresses 155, 1066 Epalinges, Switzerland.

    • Pascal Schneider

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Contributions

All authors researched the data for the article. F.B.V. wrote the manuscript and all authors reviewed/edited the manuscript before submission.

Competing interests

F.M. and E.F.M declare that they have acted as consultants for Eli Lilly and GSK. P.S. declares that he has a research agreement with Merck-Serono. F.B.V. declares no competing interests.

Corresponding author

Correspondence to Fabienne Mackay.

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https://doi.org/10.1038/nrrheum.2014.33

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