CalDAG-GEFI deficiency protects mice from FcγRIIa-mediated thrombotic thrombocytopenia induced by CD40L and β2GPI immune complexes.
CalDAG-GEFI deficiency protects mice from FcγRIIa-mediated thrombotic thrombocytopenia induced by CD40L and β2GPI immune complexes.
复制标题
DOI：
10.1111/jth.12748
复制
发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Bergmeier W
中科院分区：
文献类型：
--
作者：
Amirkhosravi A;Boulaftali Y;Robles-Carrillo L;Meyer T;McKenzie SE;Francis JL;Bergmeier W
通过Fcγ受体IIa(FcγRIIA)激活的血小板参与了免疫复合物(IC)介导的血小板减少和血栓形成的发病机制。我们以前的研究表明，由针对CD40L或β2糖蛋白I(β2GPI)的抗原和抗体组成的IC在转人FcγRIIA(HFcR)的小鼠中诱导ITT，但不能诱导野生型对照(缺乏FcγRIIA)。在这里，我们评估了鸟嘌呤核苷酸交换因子，CalDAG-GEFI和P2Y12，血小板中Rap1信号的关键调节因子，在这些临床相关ICs诱导的ITT中的作用。将预先形成的抗CD40L或抗β2GPIIC分别注射入hFcR/Caldaggef1+/+或hFcR/Caldaggef1-/-小鼠体内，加或不加氯吡格雷。观察动物休克症状30分钟，在此期间监测核心体温。分别于注射前和注射后30min测定血小板计数。通过组织学或近红外成像对肺血栓形成进行评估。CD40L和β2GPI IC均能迅速诱导hFcR/Caldaggef1+/+小鼠出现严重的血小板减少、休克和体温下降。HFcR/Caldaggef1-/-小鼠不受CD40L和β2GPI IC诱导的血小板减少和休克的影响，而抑制P2Y12对IC诱导的ITT只有轻微的影响。与这些发现一致的是，IC在体外诱导的整合素激活和IC挑战小鼠肺中活化的血小板的积累强烈依赖于CalDAG-GEFI。我们的研究表明，CalDAG-GEFI在临床相关ICs诱导的小鼠血小板活化、血小板减少和血栓形成中起关键作用。因此，CALDAG-GEFI可能是干预IC相关的、FcγRIIA介导的血栓形成条件的一个有前途的靶点。
Platelet activation via the Fcγ receptor IIa (FcγRIIa) is implicated in the pathogenesis of immune complex (IC)-mediated thrombocytopenia and thrombosis (ITT). We previously showed that ICs composed of antigen and antibodies targeting CD40 ligand (CD40L) or β2 Glycoprotein I (β2GPI) induce ITT in mice transgenic for human FcγRIIa (hFcR) but not wild-type controls (which lack FcγRIIa). Here we evaluated the contribution of the guanine nucleotide exchange factor, CalDAG-GEFI, and P2Y12, key regulators of Rap1 signaling in platelets, to ITT induced by these clinically relevant ICs. Pre-formed anti-CD40L or anti-β2GPI ICs were injected into hFcR/Caldaggef1+/+ or hFcR/Caldaggef1-/- mice, with or without clopidogrel pre-treatment. Animals were observed for symptoms of shock for 30 minutes, during which time core body temperature was monitored. Platelet counts were obtained before and 30 minutes after IC injection. Lungs were assessed for thrombosis by histology or near-infrared imaging. Both CD40L and β2GPI ICs rapidly induced severe thrombocytopenia, shock and a reduction in body temperature in hFcR/Caldaggef1+/+ mice. hFcR/Caldaggef1-/- mice were protected from CD40L and β2GPI IC-induced thrombocytopenia and shock, whereas P2Y12 inhibition had only a modest effect on IC-induced ITT. Consistent with these findings, IC-induced integrin activation in vitro and the accumulation of activated platelets in the lungs of IC-challenged mice was strongly dependent on CalDAG-GEFI. Our studies demonstrate that CalDAG-GEFI plays a critical role in platelet activation, thrombocytopenia and thrombosis induced by clinically relevant ICs in mice. Thus, CalDAG-GEFI may be a promising target for the intervention of IC-associated, FcγRIIa-mediated thrombotic conditions.
登录
查看更多内容
影响因子：
13.6
作者：
Espinosa, G;Cervera, R;Shoenfeld, Y
通讯作者：
Shoenfeld, Y
影响因子：
20.3
作者：
Polgár, J;Eichler, P;Clemetson, KJ
通讯作者：
Clemetson, KJ
影响因子：
20.3
作者：
Stolla, Moritz;Stefanini, Lucia;Bergmeier, Wolfgang
通讯作者：
Bergmeier, Wolfgang
DOI：
10.1038/nri2765
发表时间：
2010-06
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Mócsai A;Ruland J;Tybulewicz VL
通讯作者：
Tybulewicz VL
影响因子：
10.4
作者：
Meyer, T.;Robles-Carrillo, L.;Amirkhosravi, A.
通讯作者：
Amirkhosravi, A.