Abstract
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.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Adult
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Aged
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Antibodies, Monoclonal, Humanized / therapeutic use
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Arthritis, Rheumatoid / blood
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Arthritis, Rheumatoid / drug therapy
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Arthritis, Rheumatoid / immunology*
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Autoimmunity / immunology
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B-Cell Activating Factor / antagonists & inhibitors
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B-Cell Activating Factor / metabolism
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B-Cell Activation Factor Receptor / metabolism
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B-Lymphocytes, Regulatory / drug effects
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B-Lymphocytes, Regulatory / immunology*
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B-Lymphocytes, Regulatory / metabolism*
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Cells, Cultured
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Female
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Humans
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Interferon-gamma / metabolism
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Interleukin-10 / immunology
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Interleukin-10 / metabolism*
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Leukocytes, Mononuclear
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Lymphocyte Activation / drug effects
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Male
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Middle Aged
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Oligodeoxyribonucleotides / pharmacology
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Recombinant Fusion Proteins / therapeutic use
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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T-Lymphocytes / immunology
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Tumor Necrosis Factor Ligand Superfamily Member 13 / antagonists & inhibitors
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Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antibodies, Monoclonal, Humanized
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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IFNG protein, human
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IL10 protein, human
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ODN2006
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Oligodeoxyribonucleotides
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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TNFRSF13C protein, human
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TNFSF13 protein, human
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TNFSF13B protein, human
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Tumor Necrosis Factor Ligand Superfamily Member 13
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Tumor Necrosis Factor-alpha
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Interleukin-10
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belimumab
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Interferon-gamma
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TACI receptor-IgG Fc fragment fusion protein