The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies
The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies
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DOI：
10.1172/jci57850
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发表时间：
2011-11-01
影响因子：
15.9
通讯作者：
Ni, Heyu
中科院分区：
文献类型：
--
作者：
Li, Conglei;Piran, Siavash;Ni, Heyu
胎儿和新生儿免疫性血小板减少症(FNIT)是由母体抗体介导的胎儿/新生儿血小板破坏引起的一种严重的出血性疾病。它是新生儿严重血小板减少的最常见原因，但FNIT相关流产的频率尚不清楚，胎儿死亡的机制(S)也未被探索。此外，尽管血小板αIIbβ3整合素和GPIBα是免疫性血小板减少症的主要抗体靶点，但抗GPIBα介导的FNIT的报道很少。在这里，我们建立了由针对GPIBα和β3整合素的抗体介导的FNIT小鼠模型，并比较了它们的发病机制。我们意外地发现，在我们的抗GPIBα介导的FNIT模型中，大多数妊娠都发生了流产，这比抗β3介导的FNIT要频繁得多。抗GPIBα抗体阳性的DAM胎盘可见广泛的纤维蛋白沉积和细胞凋亡/坏死，严重损害胎盘功能。此外，抗GPIBα(而不是抗β3)抗血清激活了血小板，促进了体外纤维蛋白的形成和体内血栓的形成。重要的是，静脉注射免疫球蛋白或针对新生儿Fc受体的单抗有效地阻止了抗GPIBα介导的FNIT。因此，母体对胎儿GPIBα的免疫反应导致了我们认为是以前未知的、非典型的FNIT(即自发流产，但不是新生儿出血)。这些结果表明，类似的病理可能掩盖了人类抗GPIBα介导的FNIT的严重性和频率，但也指出了可能的治疗干预措施。
Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet alpha IIb beta 3 integrin and GPIb alpha are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIb alpha-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIb alpha and beta 3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIb alpha-mediated FNIT, which was far more frequent than in anti-beta 3-mediated FNIT. Dams with anti-GPIb alpha antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIb alpha (but not anti-beta 3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIb alpha-mediated FNIT. Thus, the maternal immune response to fetal GPIb alpha causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIb alpha-mediated FNIT, but also point to possible therapeutic interventions.