The Role of Decidual Innate Immunity in the Pathogenesis of Preeclampsia

描述(申请人提供)：植入人细胞滋养层细胞(CTB)侵入蜕膜，由蜕膜细胞和免疫细胞如巨噬细胞(MFS)和树突状细胞(DC)组成。这些特化的抗原提呈细胞(APC)介导先天免疫，随后激活适应性免疫系统，并在免疫耐受的发展中发挥作用。蜕膜对病原体的抵抗力和半异基因胚胎的耐受性之间的平衡失调导致了先兆子痫-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与一种异常的母体免疫反应有关，这种免疫反应限制了CTB的侵袭，并导致螺旋动脉重塑为大口径低阻力血管，这是增加子宫血流到发育中的胎儿-胎盘单位所必需的。为了支持这样的假设，即MFS和DC的过度流入和激活损害了CTB的侵袭并促进了PET，我们观察到子痫前期蜕膜中MFS和DC的显著过剩。在无白细胞的早孕蜕膜细胞中，我们发现促炎症细胞因子肿瘤坏死因子-1和白介素1-β显著增强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，从而激活未成熟的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，经IL-12处理的蜕膜细胞条件培养液可增强巨噬细胞对CTB侵袭的直接抑制作用。我们的中心假设是，促炎性细胞因子通过靶向蜕膜细胞来调节APC的运输和激活，从而有助于免疫调节和PET的发展。为了验证这一假说，我们将1)通过免疫细胞迁移分析来确定那些与招募APC有关的趋化因子；2)通过检测效应分子、激活标志物和抗原提呈活性的功能分析来确定M-CSF和GM-CSF是否在激活APC中发挥作用；3)通过CTB、APC和内皮细胞的联合培养来阐明经TNF-1或IL-12处理的蜕膜细胞对CTB侵袭和血管重构的影响；4)使用一种新型的MF或DC耗竭的PET小鼠模型来评估激活的APC在PET发育中的影响。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方法来对抗PET。因此，受影响的家庭和社会的压力和经济负担将大大减轻。与公共卫生相关：子痫前期是一种多系统疾病，导致5%至10%的妊娠并发症，是全球孕产妇和胎儿发病率和死亡率的主要原因。这项对子痫前期免疫学基础的研究将导致新的治疗方法来对抗妊娠期间的这种并发症。因此，受影响家庭和社会的福利将得到相当大的改善。

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.