Wegener's Granulomatosis: Anti–proteinase 3 Antibodies Are Potent Inductors of Human Endothelial Cell Signaling and Leakage Response
Wegener's Granulomatosis: Anti–proteinase 3 Antibodies Are Potent Inductors of Human Endothelial Cell Signaling and Leakage Response
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韦格纳肉芽肿病：抗蛋白酶 3 抗体是人内皮细胞信号传导和渗漏反应的有效诱导剂
DOI：
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发表时间：
1998
影响因子：
15.3
通讯作者：
F. Grimminger
中科院分区：
文献类型：
--
作者：
U. Sibelius;K. Hattar;Angelika Schenkel;T. Noll;E. Csernok;W. Gross;W. Mayet;H. Piper;W. Seeger;F. Grimminger
靶向蛋白酶 3 (PR3) 的抗中性粒细胞胞浆抗体 (ANCA) 对韦格纳肉芽肿病 (WG) 具有高度特异性，其在激活白细胞中的作用已得到充分认可。在本研究中，我们研究了 PR3-ANCA 和鼠单克隆抗体对人脐血管内皮细胞 (HUVEC) 的影响。通过 Cyto-ELISA 测量，用肿瘤坏死因子 α 启动 HUVEC 会诱导内皮上调 PR3 信息和该抗原的表面表达，2 小时后出现最多。引发的细胞对低浓度的两种抗体（25 ng-2.5 μg/ml）有反应，但对对照免疫球蛋白没有反应，并通过磷酸肌醇的积累来评估，具有明显的剂量依赖性磷酸肌醇水解作用。信号反应在 20 分钟后达到峰值，同时出现明显的前列环素和血小板激活因子合成。 ANCA 的 F(ab)2 片段与 ANCA 本身同样有效。通过肉毒杆菌 C2 毒素破坏内皮 F-肌动蛋白含量以避免抗原抗体内化并不影响反应。除了代谢事件外，在没有血浆成分的情况下，抗 PR3 攻击还会引起跨内皮蛋白渗漏的延迟、剂量依赖性增加。我们得出的结论是，抗 PR3 抗体是人内皮细胞中预先形成的磷酸肌醇水解相关信号转导途径的有效诱导剂。相关的代谢事件和内皮屏障特性的丧失表明，抗 PR3 诱导的内皮细胞激活可能导致以 WG 为特征的自身免疫性血管炎的发病后遗症。
Anti–neutrophil cytoplasmic antibodies (ANCAs) targeting proteinase 3 (PR3) have a high specifity for Wegener's granulomatosis (WG), and their role in activating leukocytes is well appreciated. In this study, we investigated the influence of PR3-ANCA and murine monoclonal antibodies on human umbilical vascular endothelial cells (HUVECs). Priming of HUVECs with tumor necrosis factor α induced endothelial upregulation of PR3 message and surface expression of this antigen, as measured by Cyto-ELISA, with a maximum occurrence after 2 h. Primed cells responded to low concentrations of both antibodies (25 ng–2.5 μg/ml), but not to control immunoglobulins, with pronounced, dose-dependent phosphoinositide hydrolysis, as assessed by accumulation of inositol phosphates. The signaling response peaked after 20 min, in parallel with the appearance of marked prostacyclin and platelet-activating factor synthesis. The F(ab)2 fragment of ANCA was equally potent as ANCA itself. Disrupture of the endothelial F-actin content by botulinum C2 toxin to avoid antigen–antibody internalization did not affect the response. In addition to the metabolic events, anti-PR3 challenge, in the absence of plasma components, provoked delayed, dose-dependent increase in transendothelial protein leakage. We conclude that anti-PR3 antibodies are potent inductors of the preformed phosphoinositide hydrolysis–related signal tranduction pathway in human endothelial cells. Associated metabolic events and the loss of endothelial barrier properties suggest that anti-PR3–induced activation of endothelial cells may contribute to the pathogenetic sequelae of autoimmune vasculitis characterizing WG.
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血栓调节蛋白和凝血酶在血管内皮上的定位；
影响因子：
6.6
作者：
Horvat,R;Palade,GE
通讯作者：
Palade,GE
通过将已知的人类中性粒细胞弹性蛋白酶抑制剂靶向蛋白酶 3 来研究多药理学。
影响因子：
5.6
作者：
Gartan,Parveen;Khorsand,Fahimeh;Mizar,Pushpak;Vahokovski,JuhaIlmari;Cervantes,LuisF;Haug,BengtErik;Brenk,Ruth;Brooks3rd,CharlesL;Reuter,Nathalie
通讯作者：
Reuter,Nathalie
影响因子：
158.5
作者：
FALK, RJ;JENNETTE, JC
通讯作者：
JENNETTE, JC
影响因子：
56.9
作者：
THORNTON, SC;MUELLER, SN;LEVINE, EM
通讯作者：
LEVINE, EM