Lea R G, McIntyre S, Baird J D, Clark D A
Department of Obstetrics and Gynaecology, University of Edinburgh, Scotland.
Am J Reprod Immunol. 1998 Jan;39(1):50-7. doi: 10.1111/j.1600-0897.1998.tb00333.x.
It has been proposed that high rates of resorption/spontaneous abortion may result from interaction in the decidua of gamma-interferon-producing natural killer (NK) cells and tumor necrosis factor (TNF)-alpha-producing macrophages. An increased release of TNF-alpha from placental tissue of resorptions has been reported, but macrophages producing TNF-alpha have so far not been demonstrated at the feto-maternal interface. Therefore, we have sought to identify TNF-alpha-producing cells by in situ hybridization at the feto-maternal interface in two inbred, well-characterized, and stable strains of laboratory rodents with high and low resorption rates.
Pregnant DBA/2-mated CBA/J mice with a resorption rate of 20% to 30% (dependent on NK cells and macrophages) and diabetes-resistant Bio-Breeding/Edinburgh (DR-BB/E) rats with low resorption rates (presumed to result from chromosomal abnormalities) were studied. AsialoGM1+ cells were detected by immunohistochemistry, and TNF-alpha mRNA+ cells were detected by in situ hybridization.
TNF-alpha mRNA+ cells were detected in DBA/2-mated CBA/J mice at the time of resorption but only at the trophoblast-decidual junction. AsialoGM1+ cells were present in decidua, as assessed by immunohistochemistry, but few if any gave a positive signal for TNF-alpha. In rat resorptions, TNF-alpha mRNA-positive cells were present within the yolk sac and in contact with the trophoblast, but not at the trophoblast-decidual junction. In neither species did a significant accumulation of detectable TNF-alpha mRNA+ cells occur before the usual time of onset of resorption.
In the DBA/2-mated CBA/J mouse, the removal of the placenta is associated with removal of a thin rim of adherent decidua similar to the location of the TNF-alpha mRNA+ cells detected in this study. Our data suggest that increased TNF-alpha in tissues associated with failing feto-placental units may arise from infiltration/activation of scavenger cells from decidua that are likely to be macrophages. Local TNF-alpha production in decidua, which occurs as a prelude to resorption in the CBA x DBA/2 model, could not be detected due to the insensitivity of the TNF-alpha probe we used; the release of TNF-alpha from decidual tissue left after the removal of the placenta does not differ between resorbing and healthy implant sites. AsialoGM1+ cells did not seem to be major producers of TNF-alpha. TNF-alpha mRNA+ cells in a low rate of resorption (rat) model were only found on the fetal side of the trophoblast, and they may also represent a macrophage response (to dying embryo tissue) derived from a nondecidual source. The location of TNF-alpha mRNA+ cells may identify distinct and different mechanisms of resorption in rodents.
有人提出，高吸收率/自然流产率可能是由于产生γ-干扰素的自然杀伤（NK）细胞与产生肿瘤坏死因子（TNF）-α的巨噬细胞在蜕膜中相互作用所致。据报道，吸收流产的胎盘组织中TNF-α的释放增加，但迄今为止，在母胎界面尚未证实有产生TNF-α的巨噬细胞。因此，我们试图通过原位杂交在两种近交、特征明确且稳定的实验室啮齿动物品系的母胎界面鉴定产生TNF-α的细胞，这两种品系的吸收率有高有低。
研究了吸收率为20%至30%（取决于NK细胞和巨噬细胞）的怀孕DBA/2与CBA/J交配小鼠，以及吸收率低（推测是由染色体异常导致）的抗糖尿病Bio-Breeding/Edinburgh（DR-BB/E）大鼠。通过免疫组织化学检测去唾液酸GM1+细胞，通过原位杂交检测TNF-α mRNA+细胞。
在吸收流产时，在DBA/2与CBA/J交配的小鼠中检测到TNF-α mRNA+细胞，但仅在滋养层-蜕膜交界处。通过免疫组织化学评估，去唾液酸GM1+细胞存在于蜕膜中，但很少有细胞（如果有的话）对TNF-α呈阳性信号。在大鼠吸收流产中，TNF-α mRNA阳性细胞存在于卵黄囊内并与滋养层接触，但不在滋养层-蜕膜交界处。在这两个物种中，在通常吸收流产开始时间之前，均未出现可检测到的TNF-α mRNA+细胞的显著聚集。
在DBA/2与CBA/J交配的小鼠中，胎盘的移除与附着蜕膜薄边缘的移除有关，这类似于本研究中检测到的TNF-α mRNA+细胞的位置。我们的数据表明，与胎儿-胎盘单位功能不全相关的组织中TNF-α的增加可能源于蜕膜中清除细胞（可能是巨噬细胞）的浸润/激活。在CBA×DBA/2模型中，作为吸收流产前奏的蜕膜中局部TNF-α的产生由于我们使用的TNF-α探针不敏感而未被检测到；胎盘移除后留下的蜕膜组织中TNF-α的释放，在吸收流产部位和健康着床部位之间没有差异。去唾液酸GM1+细胞似乎不是TNF-α的主要产生者。在低吸收率（大鼠）模型中，TNF-α mRNA+细胞仅在滋养层的胎儿侧被发现，它们也可能代表来自非蜕膜来源的巨噬细胞反应（对死亡胚胎组织的反应）。TNF-α mRNA+细胞的位置可能确定了啮齿动物中不同的吸收流产机制。
