A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells

J Autoimmun. 2016 Sep;73:64-72. doi: 10.1016/j.jaut.2016.06.002. Epub 2016 Jun 29.


B cells may have a negative regulatory role, mainly mediated by interleukin 10 (IL-10). We recently showed that regulatory B-cell functions are impaired in patients with rheumatoid arthritis (RA) and that mice transgenic for a proliferation-inducing ligand (APRIL) are protected against collagen-induced arthritis. We aimed to explore the effect of APRIL on human B-cell IL-10 production, in healthy subjects and in patients with RA. The IL-10 production of B-cell was greater with APRIL than with BLyS or control medium, in a dose dependent manner. TACI expression was greater in IL-10 producing B cells (B10) than non-IL-10-producing B cells whereas BAFF-R expression was lower. TNF-α and IFN-γ secretion of T-cells were decreased by APRIL-stimulated B cells. APRIL stimulated STAT3 and STAT3 inhibition decreased B10 cells. APRIL also promoted B10 cells in RA patients. In conclusion, APRIL but not BLyS promotes IL-10 production by CpG-activated B cells and enhances the regulatory role of B cells on T cells. B10 cells in RA patients are responsive to APRIL, which suggests a possible therapeutic application of APRIL to expand B10 cells. This could also explain the difference of clinical efficacy observed between belimumab and atacicept in RA.

Keywords: APRIL; B-lymphocytes; Interleukin-10; Rheumatoid arthritis.

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / immunology*
  • Autoimmunity / immunology
  • B-Cell Activating Factor / antagonists & inhibitors
  • B-Cell Activating Factor / metabolism
  • B-Cell Activation Factor Receptor / metabolism
  • B-Lymphocytes, Regulatory / drug effects
  • B-Lymphocytes, Regulatory / immunology*
  • B-Lymphocytes, Regulatory / metabolism*
  • Cells, Cultured
  • Female
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism*
  • Leukocytes, Mononuclear
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • Oligodeoxyribonucleotides / pharmacology
  • Recombinant Fusion Proteins / therapeutic use
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / antagonists & inhibitors
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibodies, Monoclonal, Humanized
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • IFNG protein, human
  • IL10 protein, human
  • ODN2006
  • Oligodeoxyribonucleotides
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TNFRSF13C protein, human
  • TNFSF13 protein, human
  • TNFSF13B protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • belimumab
  • Interferon-gamma
  • TACI receptor-IgG Fc fragment fusion protein