Sato Yoshihiro, Sugi Toshitaka, Sakai Rie
Laboratory for Recurrent Pregnancy Loss, Sugi Women's Clinic, Yokohama, Japan.
Yoshihiro Women's Clinic, Tokyo, Japan.
TH Open. 2019 Sep 3;3(3):e263-e272. doi: 10.1055/s-0039-1695709. eCollection 2019 Jul.
Factor XII (FXII) deficiency and autoantibodies that bind to FXII (anti-FXII) have been described in patients with adverse pregnancy outcomes, including recurrent pregnancy loss. It has been reported that FXII functions not only as a coagulation protein but also as a growth factor. We studied the association between anti-FXII and the epidermal growth factor (EGF) system in patients with recurrent pregnancy loss. We used synthetic peptides that span the second EGF-like domain in the heavy chain of FXII (EGF2) in inhibition and direct binding studies to determine if anti-FXII antibodies recognize EGF2. Furthermore, we examined whether anti-FXII antibodies, which recognize EGF2, also recognize recombinant EGF and heparin-binding EGF-like growth factor (HB-EGF). Among 100 patients with recurrent pregnancy loss, the plasma of 23 patients (23.0%) recognized the synthetic peptide ASQ41, which covers EGF2. Among the 23 anti-ASQ41-positive patients, plasma samples from 13 patients (56.5%) recognized the 22-residue segment C-terminal half of ASQ41. Among the 23 anti-ASQ41-positive patients, the plasma of 17 patients (73.9%) recognized recombinant human EGF. Affinity-purified anti-FXII antibodies, which recognize ASQ41, also recognized recombinant EGF family proteins such as EGF and HB-EGF. The autoantibodies in patients with recurrent pregnancy loss recognized the EGF2 domain in FXII and other proteins of the EGF family. Since proteins in the EGF family play an important role in normal pregnancy, autoantibody-associated disruption of the EGF system may cause pregnancy loss.
在包括复发性流产在内的不良妊娠结局患者中，已发现存在凝血因子Ⅻ（FXII）缺乏以及与FXII结合的自身抗体（抗FXII）。据报道，FXII不仅作为一种凝血蛋白发挥作用，还作为一种生长因子。我们研究了复发性流产患者中抗FXII与表皮生长因子（EGF）系统之间的关联。我们在抑制和直接结合研究中使用了跨越FXII重链中第二个EGF样结构域（EGF2）的合成肽，以确定抗FXII抗体是否识别EGF2。此外，我们还检测了识别EGF2的抗FXII抗体是否也识别重组EGF和肝素结合EGF样生长因子（HB-EGF）。在100例复发性流产患者中，23例患者（23.0%）的血浆识别覆盖EGF2的合成肽ASQ41。在这23例抗ASQ41阳性患者中，13例患者（56.5%）的血浆样本识别ASQ41的22个残基C末端半段。在这23例抗ASQ41阳性患者中，17例患者（73.9%）的血浆识别重组人EGF。识别ASQ41的亲和纯化抗FXII抗体也识别重组EGF家族蛋白，如EGF和HB-EGF。复发性流产患者中的自身抗体识别FXII中的EGF2结构域以及EGF家族的其他蛋白。由于EGF家族蛋白在正常妊娠中起重要作用，自身抗体相关的EGF系统破坏可能导致流产。
