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Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return
  1. Hannah Störch1,
  2. Birgit Zimmermann2,
  3. Bastian Resch1,
  4. Lars-Oliver Tykocinski1,
  5. Babak Moradi3,
  6. Patrick Horn4,
  7. Ziya Kaya5,
  8. Norbert Blank1,
  9. Stefan Rehart6,
  10. Marc Thomsen7,
  11. Hanns-Martin Lorenz1,
  12. Elena Neumann2,
  13. Theresa Tretter1
  1. 1Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
  2. 2Department of Internal Medicine and Rheumatology, University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany
  3. 3Department of Orthopaedics, Trauma Surgery and Paraplegiology, University of Heidelberg, Heidelberg, Germany
  4. 4Division of Hematology and Oncology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
  5. 5Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany
  6. 6Department of Orthopaedics and Trauma Surgery, St Markus Hospital Frankfurt, Frankfurt, Germany
  7. 7DRK Clinic for Orthopaedics, Baden-Baden, Germany
  1. Correspondence to Dr Theresa Tretter, Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, Germany; Theresa.Tretter{at}med.uni-heidelberg.de

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.

  • Fibroblasts
  • B cells
  • Inflammation
  • Rheumatoid Arthritis

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