title: A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells.
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.
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University, Montpellier, France; UMR5535, IGMM, CNRS, Montpellier, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hua
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University, Montpellier, France; UMR5535, IGMM, CNRS, Montpellier, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Audo
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Yeremenko
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baeten
authors.affiliation: UMR5535, IGMM, CNRS, Montpellier, France; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University, Montpellier, France; UMR5535, IGMM, CNRS, Montpellier, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Combe
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University, Montpellier, France; UMR5535, IGMM, CNRS, Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Morel
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University, Montpellier, France; UMR5535, IGMM, CNRS, Montpellier, France. Electronic address: c-daien@chu-montpellier.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Daïen
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C573415:IFNG protein, human; C508609:IL10 protein, human; C000615642:ODN2006; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C435926:TNFRSF13C protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C511911:belimumab; D007371:Interferon-gamma; C524618:TACI receptor-IgG Fc fragment fusion protein
keywords: APRIL; B-lymphocytes; Interleukin-10; Rheumatoid arthritis