Anti-phospholipid induced murine fetal loss: novel protective effect of a peptide targeting the β2 glycoprotein I phospholipid-binding site. Implications for human fetal loss.
Anti-phospholipid induced murine fetal loss: novel protective effect of a peptide targeting the β2 glycoprotein I phospholipid-binding site. Implications for human fetal loss.
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DOI：
10.1016/j.jaut.2011.11.009
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发表时间：
2012-05
影响因子：
12.8
通讯作者：
Meroni PL
中科院分区：
文献类型：
--
作者：
de la Torre YM;Pregnolato F;D'Amelio F;Grossi C;Di Simone N;Pasqualini F;Nebuloni M;Chen P;Pierangeli S;Bassani N;Ambrogi F;Borghi MO;Vecchi A;Locati M;Meroni PL
β2糖蛋白I（β2GPI）依赖性抗磷脂抗体（aPL）可诱导血栓形成并影响妊娠。CMV衍生的合成肽TIFI模拟β2GPI的PL结合位点，并在体外抑制β2GPI细胞结合和在体内抑制aPL介导的血栓形成。在这里，我们研究了TIFI对APL诱导的小鼠胎儿丢失的影响。采用间接免疫荧光法和ELISA法检测TIFI对体外aPL与人滋养层细胞结合的抑制作用。在用aPL或正常IgG（NHS）处理的妊娠C57 BL/6小鼠中研究TIFI对aPL诱导的胎儿丢失的作用。分析胎盘/胎儿重量和组织学以及RNA表达。TIFI，而不是对照肽VITT，显示出剂量依赖性抑制aPL结合滋养层细胞在体外。在妊娠第0天注射低剂量aPL导致生长迟缓和胎儿丢失率增加，TIFI可显著降低这两种情况，但VITT不能。与在人类中的观察结果一致，组织学分析显示在该模型中没有炎症的证据，如通过基因表达分析中不存在炎症特征所证实的，这反过来揭示了参与分化和发育过程的分子的TIFI依赖性调节。这些发现支持aPL的非炎性致病作用，并提出了针对aPL依赖性胎儿丢失的创新治疗方法。
β2 glycoprotein I (β2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of β2GPI and inhibits β2GPI cell-binding in vitro and aPL-mediated thrombosis in vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in vitro aPL binding to human trophoblasts was evaluated by indirect immunofluorescence and ELISA. TIFI effect on aPL-induced fetal loss was investigated in pregnant C57BL/6 mice treated with aPL or normal IgG (NHS). Placenta/fetus weight and histology and RNA expression were analyzed. TIFI, but not the control peptide VITT, displayed a dose-dependent inhibition of aPL binding to trophoblasts in vitro. Injection of low doses of aPL at day 0 of pregnancy caused growth retardation and increased fetal loss rate, both significantly reduced by TIFI but not VITT. Consistent with observations in humans, histological analysis showed no evidence of inflammation in this model, as confirmed by the absence of an inflammatory signature in gene expression analysis, which in turn revealed a TIFI-dependent modulation of molecules involved in differentiation and development processes. These findings support the non-inflammatory pathogenic role of aPL and suggest innovative therapeutic approaches to aPL-dependent fetal loss.
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