title: A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus.
abstract: Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an "auto"-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19(+)CD24(hi)CD38(hi) (immature) B cells into IL-10-producing CD24(+)CD38(hi) Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24(+)CD38(hi) Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24(+)CD38(hi) Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24(+)CD38(hi) Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24(+)CD38(hi) Breg cell interaction contributes to the pathogenesis of SLE.
authors.affiliation: Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK.
authors.forename: Madhvi
authors.initials: M
authors.lastname: Menon
authors.affiliation: Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Blair
authors.affiliation: Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Isenberg
authors.affiliation: Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK. Electronic address: c.mauri@ucl.ac.uk.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mauri
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D018501:Antirheumatic Agents / Q000008:administration & dosage; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000069283:Rituximab / Q000008:administration & dosage; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D018501:Antirheumatic Agents; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D000069283:Rituximab; D007371:Interferon-gamma