Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return

• Verfasst von: Ostermann, Hannah [VerfasserIn]
• Verfasst von: Resch, Bastian [VerfasserIn]
• Verfasst von: Tykocinski, Lars-Oliver [VerfasserIn]
• Verfasst von: Moradi, Babak [VerfasserIn]
• Verfasst von: Horn, Patrick [VerfasserIn]
• Verfasst von: Kaya, Ziya [VerfasserIn]
• Verfasst von: Blank, Norbert [VerfasserIn]
• Verfasst von: Lorenz, Hanns-Martin [VerfasserIn]
• Verfasst von: Tretter, Theresa [VerfasserIn]
• Titel: Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return
• Verf.angabe: 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
• Jahr: 2016
• Umfang: 9 S.
• Fussnoten: Published online first 18 May 2015 ; Gesehen am 19.05.2020
• Titel Quelle: Enthalten in: Annals of the rheumatic diseases
• Ort Quelle: London : BMJ Publ. Group, 1939
• Jahr Quelle: 2016
• Band/Heft Quelle: 75(2016), 5, Seite 924-932
• ISSN Quelle: 1468-2060
• DOI: doi:10.1136/annrheumdis-2014-206965
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: B cells
• Sach-SW: Fibroblasts
• Sach-SW: Inflammation
• Sach-SW: Rheumatoid Arthritis
• K10plus-PPN: 169851963X

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.