Abrahams Vikki M, Visintin Irene, Aldo Paulomi B, Guller Seth, Romero Roberto, Mor Gil
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
J Immunol. 2005 Dec 15;175(12):8096-104. doi: 10.4049/jimmunol.175.12.8096.
Normal pregnancy is characterized by the presence of innate immune cells at the maternal-fetal interface. Originally, it was postulated that the presence of these leukocytes was due to an immune response toward paternal Ags expressed by the invading trophoblasts. Instead, we and others postulate that these innate immune cells are necessary for successful implantation and pregnancy. However, elevated leukocyte infiltration may be an underlying cause of pregnancy complications, such as preterm labor or preeclampsia. Furthermore, such conditions have been attributed to an intrauterine infection. Therefore, we hypothesize that first trimester trophoblast cells, upon recognition of microbes through TLRs, may coordinate an immune response by recruiting cells of the innate immune system to the maternal-fetal interface. In this study, we have demonstrated that human first trimester trophoblast cells constitutively secrete the chemokines growth-related oncogene, growth-related oncogene alpha, IL-8, and MCP-1 and are able to recruit monocytes and NK cells, and to a lesser degree, neutrophils. Following the ligation of TLR-3 by the viral ligand, poly(I:C), or TLR-4 by bacterial LPS, trophoblast secretion of chemokines is significantly increased and this in turn results in elevated monocyte and neutrophil chemotaxis. In addition, TLR-3 stimulation also induces trophoblast cells to secrete RANTES. These results suggest a novel mechanism by which first trimester trophoblast cells may differentially modulate the maternal immune system during normal pregnancy and in the presence of an intrauterine infection. Such altered trophoblast cell responses might contribute to the pathogenesis of certain pregnancy complications.
正常妊娠的特征是母胎界面存在固有免疫细胞。最初，有人推测这些白细胞的存在是由于对侵入的滋养层细胞表达的父源抗原产生免疫反应。相反，我们和其他人推测这些固有免疫细胞是成功着床和妊娠所必需的。然而，白细胞浸润增加可能是妊娠并发症（如早产或子痫前期）的潜在原因。此外，这些情况被认为与宫内感染有关。因此，我们假设孕早期滋养层细胞在通过Toll样受体（TLR）识别微生物后，可能通过将固有免疫系统细胞募集到母胎界面来协调免疫反应。在本研究中，我们已经证明人类孕早期滋养层细胞组成性分泌趋化因子生长相关癌基因、生长相关癌基因α、白细胞介素-8和单核细胞趋化蛋白-1，并能够募集单核细胞和自然杀伤细胞，在较小程度上还能募集中性粒细胞。在病毒配体聚肌苷酸-聚胞苷酸（poly(I:C)）连接TLR-3或细菌脂多糖连接TLR-4后，滋养层细胞趋化因子的分泌显著增加，这反过来导致单核细胞和中性粒细胞趋化性升高。此外，TLR-3刺激还诱导滋养层细胞分泌调节激活正常T细胞表达和分泌的因子（RANTES）。这些结果提示了一种新机制，通过该机制孕早期滋养层细胞在正常妊娠期间以及存在宫内感染时可能差异性地调节母体免疫系统。这种滋养层细胞反应的改变可能有助于某些妊娠并发症的发病机制。
