Impact of Mast cells on synovial inflammation and bone destruction in autoimmune-induced arthritis

肥大细胞对自身免疫性关节炎滑膜炎症和骨破坏的影响

• 批准号: 169442275
• 负责人: Professorin Dr. Anne Dudeck
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/169442275?language=en
• 关键词: Impact; Mast; cells; synovial; inflammation

Mast cells (MCs) play a critical role in innate immunity and in the induction of adaptive immune responses. Increasing evidence suggests that MCs also have an important impact on the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). The inflamed synovial tissue of RA-patients is characterized by a massive accumulation of MCs which correlates with the intensity of the joint inflammation. Furthermore, the intensified osteoclast differentiation as a hallmark of arthritis-induced bone destruction is modulated by proinflammatory mediators including RANKL, TNF, IL-1, IL-6 and IFN-g, all of which are known to be produced and secreted by MCs. This proposal addresses the role of MCs in synovial inflammation as well as cartilage and bone destruction. For this purpose, we will study the model of K/BxN serum transfer-induced arthritis in vivo in transgenic mice characterized by a selective depletion of MCs or by MC-specific inactivation of genes encoding cytokines or growth factors. Moreover, we will assess the capability of MCs to induce or modulate osteoclast differentiation in vitro and in vivo. Finally, we will establish a technique to visualize cellular interactions of MCs with joint infiltrating neutrophils or T cells directly in the inflamed joint by intravital 2-Photon-Microscopy. Understanding the mast celldriven effects on the arthritis-induced synovial inflammation and bone destruction may be of great importance to identify new targets for therapeutic strategies.

肥大细胞（MCs）在先天免疫和诱导适应性免疫应答中起着关键作用。越来越多的证据表明，MCs也对包括类风湿性关节炎（RA）在内的自身免疫性疾病的发病机制有重要影响。ra患者的滑膜组织炎症的特征是MCs的大量积累，这与关节炎症的强度相关。此外，作为关节炎引起的骨破坏的标志，破骨细胞分化的加剧受到促炎介质的调节，包括RANKL、TNF、IL-1、IL-6和IFN-g，所有这些介质都是由MCs产生和分泌的。这一建议解决了MCs在滑膜炎症以及软骨和骨破坏中的作用。为此，我们将在转基因小鼠体内研究K/BxN血清转移诱导的关节炎模型，其特征是mc的选择性消耗或mc特异性编码细胞因子或生长因子的基因失活。此外，我们将评估MCs在体外和体内诱导或调节破骨细胞分化的能力。最后，我们将建立一种技术，通过活体2光子显微镜直接观察炎症关节中MCs与浸润性中性粒细胞或T细胞的细胞相互作用。了解肥大细胞对关节炎诱导的滑膜炎症和骨破坏的影响可能对确定新的治疗策略靶点具有重要意义。