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首页> 外文期刊>Arthritis & Rheumatism >C5a receptor enables participation of mast cells in immune complex arthritis independently of Fc receptor modulation
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C5a receptor enables participation of mast cells in immune complex arthritis independently of Fc receptor modulation

机译：C5a受体使肥大细胞参与免疫性复杂性关节炎，而与Fc受体的调节无关

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摘要

ObjectiveMast cells are tissue-resident immune sentinels that are implicated in the pathogenesis of inflammatory joint disease. The aim of this study was to test our hypothesis that complement fragments could be key activators of synovial mast cells in autoimmune arthritis.MethodsIn vivo studies used the murine K/BxN arthritis model, a distal symmetric polyarthritis mediated by IgG immune complexes. Expression of C5aR on synovial mast cells was determined by immunohistochemical and functional studies. C5aR−/− and control mast cells were engrafted into mast cell–deficient WBB6 F1-Kitw/KitW-v (W/Wv) mice to examine the requirement for this receptor in arthritis. C5aR-dependent activation of mast cells was investigated in C5aR−/− animals and in murine and human mast cell cultures.ResultsMurine synovial mast cells express functional C5aR. Unlike their wild-type counterparts, C5aR−/− mast cells adoptively transferred into W/Wv mice were not competent to restore arthritis, despite equivalent synovial engraftment. Activation of C5aR−/− mast cells by K/BxN serum in vivo remained intact, indicating that C5aR is dispensable for normal IgG-mediated triggering. Consistent with this result, cultured mast cells treated with C5a failed to modulate the expression of Fc receptors (FcR) or to otherwise alter the activation threshold. In human mast cells, C5a promoted the production of the neutrophil chemotaxin interleukin-8, and recruitment of neutrophils at 24 hours after serum administration was impaired in C5aR−/− mice, suggesting that enhanced neutrophil chemoattractant production underlies the requirement for C5aR on mast cells in arthritis.ConclusionStimulation via C5aR is required to unleash the proinflammatory activity of synovial mast cells in immune complex arthritis, albeit via a mechanism that is distinct from C5a-modulated expression of FcR.
机译：目的肥大细胞是组织固有的免疫前哨，与炎症性关节疾病的发病机制有关。这项研究的目的是检验我们的假设，即补体片段可能是自身免疫性关节炎中滑膜肥大细胞的关键激活剂。方法体内研究使用鼠K / BxN关节炎模型，一种由IgG免疫复合物介导的远端对称性多关节炎。通过免疫组织化学和功能研究确定滑膜肥大细胞上C5aR的表达。将C5aR -/-和对照肥大细胞移植到缺乏肥大细胞的WBB6 F1-Kit w / Kit Wv （W / Wv）小鼠中检查关节炎中对该受体的需求。研究了C5aR -/-动物以及鼠和人肥大细胞培养物中肥大细胞的C5aR依赖性激活。结果鼠滑膜肥大细胞表达功能性C5aR。与野生型对应物不同，尽管滑膜植入程度相同，但过继转移至W / Wv小鼠的C5aR -/-肥大细胞不能恢复关节炎。体内K / BxN血清对C5aR -/-肥大细胞的激活仍保持完整，表明C5aR对于正常的IgG介导的触发是可有可无的。与该结果一致，用C5a处理的培养的肥大细胞不能调节Fc受体（FcR）的表达或不能改变激活阈值。在人类肥大细胞中，C5a促进了中性粒细胞趋化因子白细胞介素8的产生，并且在C5aR -/-小鼠中血清给药后24小时中性粒细胞的募集受到损害，这表明中性粒细胞趋化因子的产生可能是基础结论C5aR刺激是在免疫复合物关节炎中释放滑膜肥大细胞的促炎活性，尽管其机制不同于C5a调节的FcR表达。

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  • 来源
    《Arthritis & Rheumatism》 |2010年第11期|p.3322-3333|共12页
  • 作者

    Peter A. Nigrovic; Odile Malbec; Bao Lu; Maciej M. Markiewski; Chris Kepley; Norma Gerard; Craig Gerard; Marc Daëron; David M. Lee;

  • 作者单位

    Brigham and Women's Hospital and Children's Hospital Boston, Boston, Massachusetts;

    Institut Pasteur and INSERM U760, Paris, France;

    Children's Hospital Boston, Boston, Massachusetts;

    University of Pennsylvania, Philadelphia;

    Luna Innovations, Inc., Danville, Virginia;

    Children's Hospital Boston, Boston, Massachusetts;

    Children's Hospital Boston, Boston, Massachusetts;

    |Institut Pasteur and INSERM U760, Paris, France;

    Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts|;

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