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

@entity1 @entity32 @entity650 @entity7382 @entity571 @entity5 @entity310 @entity19 @entity1549 @entity465 @entity1192 @entity2902 @entity687 @entity309 @entity19646
BACKGROUND: Cross-talk between synovial fibroblasts (SF) and immune cells is suggested to play a crucial role in @entity32 and chronification of @entity309 ( @entity309 ). 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 @entity1 with @entity571 . RESULTS: In B-SF cocultures the concentrations of @entity650 ( @entity650 ) and @entity687 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 @entity650 and @entity687 , and B cells as main producers of @entity5 necrosis factor alpha ( @entity310 ) and @entity1192  . Blocking experiments with a combination of anti- @entity310 -antibodies and @entity19646 significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived @entity310 and @entity1192   were crucial mediators of SF activation. Interestingly, B-cell cytokine production, @entity2902 expression and proliferation decreased in cocultures by at least 50%, demonstrating a negative regulatory loop towards the activated B cells. Inhibition of @entity7382 , a crucial component of the @entity5 growth factor    (TGF  ) signalling pathway, partly restored B-cell proliferation, suggesting a contribution of SF-derived TGF   in B-cell suppression. Besides cytokines, B-cell-activated SF also upregulated secretion of matrix metalloproteases such as @entity1549 , thereby acquiring potential tissue destructive properties. This was confirmed by their invasion into @entity1 cartilage in the severe combined @entity465 @entity19 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 @entity309 -like phenotype, thereby suggesting a new, so far unrecognised role for B cells in @entity309 pathogenesis.
