Kneilling Manfred, Hültner Lothar, Pichler Bernd J, Mailhammer Reinhard, Morawietz Lars, Solomon Samuel, Eichner Martin, Sabatino Joseph, Biedermann Tilo, Krenn Veit, Weber Wolfgang A, Illges Harald, Haubner Roland, Röcken Martin
Eberhard Karls University, Tübingen, Germany.
Arthritis Rheum. 2007 Jun;56(6):1806-16. doi: 10.1002/art.22602.
Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis.
Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse-derived serum or control serum in wild-type Kit(+)/Kit(+) mice, congenic mast cell-deficient Kit(W)/Kit(W-v) mice, or mast cell-deficient Kit(W)/Kit(W-v) mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated alphavbeta3 integrin using (18)F-galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, beta3, and alpha-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice.
Comparing wild-type mice, mast cell-deficient Kit(W)/Kit(W-v) mice, and mast cell-reconstituted Kit(W)/Kit(W-v) mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and alphavbeta3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented alphavbeta3 integrin activation, angiogenesis, and joint destruction.
Mast cell engraftment fully restores susceptibility to alphavbeta3 integrin activation, angiogenesis, and joint destruction in GPI antibody-induced arthritis. Importantly, selective mast cell stabilization prevents alphavbeta3 integrin activation, angiogenesis, and joint destruction.
用抗葡萄糖-6-磷酸异构酶（GPI）自身抗体诱导关节炎完全不依赖T细胞和B细胞，但严格依赖肥大细胞的存在。在此，我们使用该疾病模型分析单纯关节内肥大细胞重建是否足以诱导疾病，以及靶向肥大细胞沉默是否能预防类风湿关节炎的两个标志——新生血管形成和关节破坏。
在野生型Kit(+)/Kit(+)小鼠、同基因肥大细胞缺陷型Kit(W)/Kit(W-v)小鼠或经肥大细胞重建的肥大细胞缺陷型Kit(W)/Kit(W-v)小鼠（通过腹腔注射或选择性关节内注射）中，注射K/BxN小鼠来源的血清或对照血清后，测定踝关节肿胀和临床指数评分。通过使用(18)F-半乳糖-RGD和正电子发射断层扫描测量活化的αvβ3整合素来体内定量血管生成。此外，对关节组织进行苏木精和伊红、吉姆萨、β3和α-肌动蛋白染色。在C57BL/6或BALB/c小鼠中研究用色甘酸钠或沙丁胺醇治疗使肥大细胞稳定的效果。
比较野生型小鼠、肥大细胞缺陷型Kit(W)/Kit(W-v)小鼠和肥大细胞重建的Kit(W)/Kit(W-v)小鼠，我们首先表明关节内和腹腔内肥大细胞植入完全恢复了对抗体诱导的关节炎、血管生成和αvβ3整合素活化的易感性。重要的是，用沙丁胺醇或色甘酸钠进行选择性肥大细胞沉默可预防αvβ3整合素活化、血管生成和关节破坏。
肥大细胞植入完全恢复了GPI抗体诱导的关节炎中对αvβ3整合素活化、血管生成和关节破坏的易感性。重要的是，选择性肥大细胞稳定可预防αvβ3整合素活化、血管生成和关节破坏。
