The Role of Decidual Innate Immunity in the Pathogenesis of Preeclampsia

描述（由申请人提供）：植入人细胞滋养细胞（CTBs）侵入由蜕膜细胞和免疫细胞如巨噬细胞（MFs）和树突状细胞（DCs）组成的底层蜕膜。这些特殊的抗原呈递细胞（APCs）介导先天免疫，随后的适应性免疫系统的激活和免疫耐受的发展。在蜕膜中，对病原体的防御和对半异体胚胎的耐受之间的平衡受到干扰会导致子痫前期毒血症（PET），这是围产期和孕产妇发病率和死亡率的主要原因。PET与异常的母体免疫反应有关，该反应限制了CTB的侵袭，并导致螺旋动脉重构受损，而螺旋动脉重构为大孔低阻力血管是增加子宫血液流向发育中的胎儿-胎盘单元所必需的。为了支持MFs和dc的过量内流和激活损害CTB侵袭并促进PET的假设，我们在子痫前期蜕膜中观察到MFs和dc的明显过量。在无白细胞的妊娠早期蜕细胞中，我们发现促炎细胞因子、肿瘤坏死因子-1 （TNF-1）和白细胞介素-1 β (IL-12)显著增强了巨噬细胞集落刺激因子（M-CSF）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）的表达，这些因子可激活未成熟的MFs和dc向成熟的MFs和dc以及一系列单核/巨噬细胞和dc募集趋化因子。我们还发现，il -12处理的蜕细胞培养的条件培养基增强了巨噬细胞对CTB侵袭的直接抑制。我们的中心假设是，促炎细胞因子通过靶向蜕细胞来失调apc的运输和激活，从而促进免疫调节和PET的发展。为了验证这一假设，我们将1)使用免疫细胞迁移试验确定负责招募apc的趋化因子；2)通过检测效应分子、激活标记物和抗原提呈活性的功能测定，确定M-CSF和GM-CSF是否在激活APCs中发挥作用；3)通过CTBs、APCs和内皮细胞共培养研究TNF-1或IL-12处理的蜕细胞对CTB侵袭和血管重构的影响；4)利用一种新型的MF或dc缺失PET小鼠模型来评估活化apc对PET发育的影响。这项工作将有助于更好地了解PET的发病机制，并开发有效的预防和治疗PET的方法。因此，受影响家庭和社会的压力和经济负担将大大减轻。公共卫生相关性：先兆子痫是一种多系统疾病，在所有妊娠中占5%至10%，是全世界孕产妇和胎儿发病率和死亡率的主要原因。这项研究的免疫学基础的先兆子痫将导致新的治疗方法，以对抗这种并发症在怀孕期间。因此，受影响家庭和社会的福利将大大改善。

DESCRIPTION (provided by applicant): Implanting human cytotrophoblasts (CTBs) invade an underlying decidua comprised of decidual cells and such immune cells as macrophages (MFs) and dendritic cells (DCs). These specialized antigen-presenting cells (APCs) mediate innate immunity, subsequent activation of the adaptive immune system and in the development of immune tolerance. Perturbation of the balance between defense against pathogens and tolerance of the semi-allogeneic embryo in the decidua contributes to preeclampsia-toxemia (PET), a leading cause of perinatal and maternal morbidity and mortality. PET is associated with an aberrant maternal immune response that restricts CTB invasion and leads to impaired remodeling of the spiral arteries into large bore low resistance vessels necessary to increase uterine blood flow to the developing feto-placental unit. In support of the hypothesis that an excess influx and activation of MFs and DCs impair CTB invasion and promotes PET, we observed a marked excess of MFs and DCs in preeclamptic decidua. In leukocyte-free first trimester decidual cells, we found that the pro-inflammatory cytokines, tumor necrosis factor-a (TNF-1) and interleukin-1 beta (IL-12), profoundly enhanced expression of macrophage-colony stimulating factor (M-CSF), granulocyte- macrophage-colony stimulating factor (GM-CSF), which activate immature MFs and DCs to mature MFs and DCs as well as an array of monocyte/macrophage- and DC-recruiting chemokines. We also found that the direct inhibition of CTB invasion by macrophages was enhanced by conditioned media from IL-12-treated decidual cell culture. Our central hypothesis is that pro-inflammatory cytokines dysregulate trafficking and activation of APCs by targeting decidual cells and, thus, contribute to the immune modulation and the development of PET. To test this hypothesis, we will 1) identify those chemokines responsible for recruiting APCs using immune cell migration assays; 2) determine whether M-CSF and GM-CSF play roles in activating APCs by examining effector molecules, activation markers and functional assays for antigen-presenting activity; 3) elucidate the effects of TNF-1 - or IL-12 -treated decidual cells on CTB invasion and vascular remodeling using co-culture of CTBs, APCs and endothelial cells; 4) use a novel MF- or DC-depleted PET mouse model to evaluate the effects of activated APCs on the development of PET. This work will lead to better understanding of the pathogenesis of PET and the development of effective prevention and therapies to combat PET. Consequently, stress and financial burden for affected family and society will be significantly reduced. PUBLIC HEALTH RELEVANCE: Preeclampsia is a multi-system disorder that complicates 5% to 10% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality worldwide. This study of the immunological basis of preeclampsia will result in new therapies to combat this complication during pregnancy. Hence, the welfare of affected families and society will be considerably improved.