BAFF inhibition in SLE-Is tolerance restored?

Immunol Rev. 2019 Nov;292(1):102-119. doi: 10.1111/imr.12810. Epub 2019 Sep 28.


The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF-like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low-affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM- and IgG-producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.

Keywords: B cells; BAFF; SLE; selection; tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • B-Cell Activating Factor / antagonists & inhibitors*
  • B-Cell Activating Factor / immunology
  • B-Cell Activating Factor / metabolism
  • Humans
  • Immune Tolerance / drug effects*
  • Immune Tolerance / immunology
  • Immunosuppressive Agents / therapeutic use
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism
  • Receptors, Antigen, B-Cell / immunology
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / immunology
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism


  • Antibodies, Monoclonal, Humanized
  • B-Cell Activating Factor
  • Immunosuppressive Agents
  • Receptors, Antigen, B-Cell
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • belimumab