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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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Hauptverfasser: Ostermann, Hannah (VerfasserIn) , Resch, Bastian (VerfasserIn) , Tykocinski, Lars-Oliver (VerfasserIn) , Moradi, Babak (VerfasserIn) , Horn, Patrick (VerfasserIn) , Kaya, Ziya (VerfasserIn) , Blank, Norbert (VerfasserIn) , Lorenz, Hanns-Martin (VerfasserIn) , Tretter, Theresa (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2016
In: Annals of the rheumatic diseases
Year: 2016, Jahrgang: 75, Heft: 5, Pages: 924-932
ISSN:1468-2060
DOI:10.1136/annrheumdis-2014-206965
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/annrheumdis-2014-206965
Verlag, lizenzpflichtig, Volltext: https://ard.bmj.com/content/75/5/924
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Published online first 18 May 2015
Gesehen am 19.05.2020
Beschreibung:Online Resource
ISSN:1468-2060
DOI:10.1136/annrheumdis-2014-206965

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