PMID- 25985971 OWN - NLM STAT- MEDLINE DCOM- 20160829 LR - 20160409 IS - 1468-2060 (Electronic) IS - 0003-4967 (Linking) VI - 75 IP - 5 DP - 2016 May TI - Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return. PG - 924-32 LID - 10.1136/annrheumdis-2014-206965 [doi] AB - 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 (TNFalpha) and IL-1ss. Blocking experiments with a combination of anti-TNFalpha-antibodies and rIL-1RA significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived TNFalpha 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. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ FAU - Storch, Hannah AU - Storch H AD - Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. FAU - Zimmermann, Birgit AU - Zimmermann B AD - Department of Internal Medicine and Rheumatology, University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany. FAU - Resch, Bastian AU - Resch B AD - Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. FAU - Tykocinski, Lars-Oliver AU - Tykocinski LO AD - Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. FAU - Moradi, Babak AU - Moradi B AD - Department of Orthopaedics, Trauma Surgery and Paraplegiology, University of Heidelberg, Heidelberg, Germany. FAU - Horn, Patrick AU - Horn P AD - Division of Hematology and Oncology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. FAU - Kaya, Ziya AU - Kaya Z AD - Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany. FAU - Blank, Norbert AU - Blank N AD - Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. FAU - Rehart, Stefan AU - Rehart S AD - Department of Orthopaedics and Trauma Surgery, St Markus Hospital Frankfurt, Frankfurt, Germany. FAU - Thomsen, Marc AU - Thomsen M AD - DRK Clinic for Orthopaedics, Baden-Baden, Germany. FAU - Lorenz, Hanns-Martin AU - Lorenz HM AD - Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. FAU - Neumann, Elena AU - Neumann E AD - Department of Internal Medicine and Rheumatology, University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany. FAU - Tretter, Theresa AU - Tretter T AD - Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150518 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-1beta) RN - 0 (Transforming Growth Factor beta) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.4.24.- (Matrix Metalloproteinases) SB - IM MH - Animals MH - Arthritis, Rheumatoid/immunology MH - B-Lymphocytes/*immunology MH - Cartilage, Articular/*immunology MH - Coculture Techniques MH - Cytokines/biosynthesis MH - Fibroblasts/*immunology MH - Heterografts MH - Humans MH - Immune Tolerance/immunology MH - Inflammation Mediators/metabolism MH - Interleukin-1beta/immunology MH - Lymphocyte Activation/*immunology MH - Matrix Metalloproteinases/biosynthesis MH - Mice, SCID MH - Osteoarthritis/*immunology MH - Signal Transduction/immunology MH - Synovial Fluid/immunology MH - Transforming Growth Factor beta/immunology MH - Tumor Necrosis Factor-alpha/immunology OTO - NOTNLM OT - B cells OT - Fibroblasts OT - Inflammation OT - Rheumatoid Arthritis EDAT- 2015/05/20 06:00 MHDA- 2016/08/30 06:00 CRDT- 2015/05/20 06:00 PHST- 2014/11/10 00:00 [received] PHST- 2015/04/26 00:00 [accepted] PHST- 2015/05/20 06:00 [entrez] PHST- 2015/05/20 06:00 [pubmed] PHST- 2016/08/30 06:00 [medline] AID - annrheumdis-2014-206965 [pii] AID - 10.1136/annrheumdis-2014-206965 [doi] PST - ppublish SO - Ann Rheum Dis. 2016 May;75(5):924-32. doi: 10.1136/annrheumdis-2014-206965. Epub 2015 May 18.