Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return
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 polycl...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2016
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| In: |
Annals of the rheumatic diseases
Year: 2016, Volume: 75, Issue: 5, Pages: 924-932 |
| ISSN: | 1468-2060 |
| DOI: | 10.1136/annrheumdis-2014-206965 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/annrheumdis-2014-206965 Verlag, lizenzpflichtig, Volltext: https://ard.bmj.com/content/75/5/924 
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| Author Notes: | Hannah Störch, Birgit Zimmermann, Bastian Resch, Lars-Oliver Tykocinski, Babak Moradi, Patrick Horn, Ziya Kaya, Norbert Blank, Stefan Rehart, Marc Thomsen, Hanns-Martin Lorenz, Elena Neumann, Theresa Tretter |
| Summary: | 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. |
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| Item Description: | Published online first 18 May 2015 Gesehen am 19.05.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1468-2060 |
| DOI: | 10.1136/annrheumdis-2014-206965 |