title: Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return.
abstract: BACKGROUND
  Cross-talk between synovial fibroblasts (SF) and immune cells is suggested to play a crucial role in inflammation and chronification of rheumatoid arthritis (RA). The contribution of B cells in this process is poorly defined.
  
  
  METHODS
  Here, primary B cells from healthy donors were polyclonally activated and cocultured with SF of non-synovitic origin from patients with osteoarthritis.
  
  
  RESULTS
  In B-SF cocultures the concentrations of interleukin 6 (IL-6) and IL-8 increased manifold compared with single cultures even under physical separation and remained stable for several days after B-cell removal. Intracellular staining confirmed SF as key producers of IL-6 and IL-8, and B cells as main producers of tumour necrosis factor alpha (TNFα) and IL-1ß. Blocking experiments with a combination of anti-TNFα-antibodies and rIL-1RA significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived TNFα and IL-1ß were crucial mediators of SF activation. Interestingly, B-cell cytokine production, CD25 expression and proliferation decreased in cocultures by at least 50%, demonstrating a negative regulatory loop towards the activated B cells. Inhibition of activin receptor-like kinase 5, a crucial component of the tumour growth factor ß (TGFß) signalling pathway, partly restored B-cell proliferation, suggesting a contribution of SF-derived TGFß in B-cell suppression. Besides cytokines, B-cell-activated SF also upregulated secretion of matrix metalloproteases such as MMP-3, thereby acquiring potential tissue destructive properties. This was confirmed by their invasion into human cartilage in the severe combined immunodeficiency mouse fibroblast invasion model in vivo.
  
  
  CONCLUSIONS
  Interaction with activated B cells leads to conversion of non-arthritic SF into SF with a proinflammatory and aggressive RA-like phenotype, thereby suggesting a new, so far unrecognised role for B cells in RA pathogenesis.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Störch
authors.affiliation: Department of Internal Medicine and Rheumatology, University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Zimmermann
authors.affiliation: Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Resch
authors.affiliation: Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Tykocinski
authors.affiliation: Department of Orthopaedics, Trauma Surgery and Paraplegiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Babak
authors.initials: B
authors.lastname: Moradi
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Horn
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ziya
authors.initials: Z
authors.lastname: Kaya
authors.affiliation: Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Blank
authors.affiliation: Department of Orthopaedics and Trauma Surgery, St Markus Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rehart
authors.affiliation: DRK Clinic for Orthopaedics, Baden-Baden, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Thomsen
authors.affiliation: Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hanns-Martin
authors.initials: HM
authors.lastname: Lorenz
authors.affiliation: Department of Internal Medicine and Rheumatology, University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Neumann
authors.affiliation: Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Tretter
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002358:Cartilage, Articular / Q000276:immunology*; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000276:immunology*; D064593:Heterografts; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D016513:Mice, SCID; D010003:Osteoarthritis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases
keywords: B cells; Fibroblasts; Inflammation; Rheumatoid Arthritis