Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return
Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return
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DOI：
10.1136/annrheumdis-2014-206965
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发表时间：
2015-05
影响因子：
27.4
通讯作者：
Hannah Störch;B. Zimmermann;B. Resch;L. Tykocinski;B. Moradi;P. Horn;Z. Kaya;N. Blank;S. Rehart;M. Thomsen;H. Lorenz;E. Neumann;T. Tretter
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文献类型：
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作者：
Hannah Störch;B. Zimmermann;B. Resch;L. Tykocinski;B. Moradi;P. Horn;Z. Kaya;N. Blank;S. Rehart;M. Thomsen;H. Lorenz;E. Neumann;T. Tretter
背景滑膜成纤维细胞（SF）和免疫细胞之间的相互作用在类风湿关节炎（RA）的炎症和慢性化中起着至关重要的作用。B细胞在此过程中的作用尚不明确。方法将健康人的原代B细胞多克隆活化，与骨关节炎患者的非滑膜来源的SF共培养。结果B-SF共培养液中IL-6和IL-8的浓度比单一培养液中的IL-6和IL-8的浓度增加了许多倍，即使在物理分离的情况下，在去除B细胞后的几天内仍保持稳定。细胞内染色证实SF是IL-6和IL-8的主要产生者，B细胞是肿瘤坏死因子α（TNFα）和IL-1 β的主要产生者。联合使用抗TNF α抗体和rIL-1 RA的阻断实验可显著降低SF细胞因子的产生达90%，表明B细胞源性TNFα和IL-1 RA是SF活化的关键介质。有趣的是，共培养物中B细胞细胞因子产生、CD 25表达和增殖降低至少50%，表明对活化的B细胞的负调节环。抑制激活素受体样激酶5，肿瘤生长因子β（TGF β）信号通路的关键组成部分，部分恢复B细胞增殖，表明SF衍生的TGF β在B细胞抑制中的贡献。除了细胞因子，B细胞活化的SF还上调基质金属蛋白酶如MMP-3的分泌，从而获得潜在的组织破坏性。在严重联合免疫缺陷小鼠成纤维细胞体内侵袭模型中，它们侵入人软骨证实了这一点。结论与活化的B细胞的相互作用导致非关节炎性SF转化为具有促炎性和侵袭性RA样表型的SF，从而提示B细胞在RA发病机制中的新的、迄今未被认识的作用。
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.