CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages.
CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages.
复制标题
CD39 和 CD73 活性在抗磷脂抗体诱导的流产小鼠模型中具有保护作用。
DOI：
10.1016/j.jaut.2017.10.009
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发表时间：
2018
影响因子：
12.8
通讯作者：
Nandurkar,HarshalH
中科院分区：
文献类型：
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作者：
Samudra,AnushkaN;Dwyer,KarenM;Selan,Carly;Freddi,Susanna;Murray-Segal,Lisa;Nikpour,Mandana;Hickey,MichaelJ;Peter,Karlheinz;Robson,SimonC;Sashindranath,Maithili;Cowan,PeterJ;Nandurkar,HarshalH
抗磷脂综合征（APS）是一种全身性自身免疫性疾病的年轻人与毁灭性的妊娠并发症（复发性流产，先兆子痫和低出生体重）和血管并发症，包括血栓形成。APS发病机制中涉及的关键成分是引起炎症和凝血的补体级联和组织因子（TF）活性。涉及ATP通过细胞表面酶CD 39和CD 73催化转化为腺苷的嘌呤能信号传导具有抗炎和抗血栓形成作用。我们研究了CD 39和CD 73的活性是否在预防APS中流产的发展中是重要的。方法我们研究了将人aPL-ab被动转移到妊娠野生型小鼠和CD 39和CD 73缺陷的小鼠后流产和蜕膜病理学的频率，结果在妊娠的CD 39-或CD 73-敲除小鼠中输注PL-ab引发流产增加，与胎盘蜕膜内TF表达和补体沉积增加以及氧化应激和促炎性TNF-α和IL-10表达升高相关。相比之下，aPL-ab诱导的流产在过表达CD 39的小鼠中得到预防，蜕膜TF表达和C3 d沉积减少，脂质过氧化减少，（4-羟基壬烯醛或4-HNE阳性脂质加合物），结论CD 39在APS中具有保护作用，并为APS中内皮细胞的发育提供了理论基础。靶向可溶性CD 39作为APS的新型治疗剂，并分析嘌呤能途径的扰动以解释人类疾病。
ObjectiveAntiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preeclampsia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS.MethodsWe studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity.ResultsaPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression.ConclusionWe demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.