本文選題：反復(fù)種植失敗　切入點：分泌期內(nèi)膜　出處：《鄭州大學(xué)》2017年碩士論文

【摘要】：研究背景反復(fù)種植失敗(repeated implant failure,RIF)的具體分子機制尚不十分明確,目前已知2/3的RIF是由子宮內(nèi)膜容受性失調(diào)引起的,究其原因可能與免疫相關(guān),已有的免疫學(xué)研究表明,妊娠是一種同種異體排斥現(xiàn)象,正常妊娠的胚胎,為半同體組織抗原不被母體排斥影響而生存,蛻膜組織與正常免疫微環(huán)境有一定關(guān)聯(lián)。子宮自然殺傷細胞(uterine natural killer cell,uNK)是子宮內(nèi)膜特有的自然殺傷(NK)細胞,表面特異性標記是CD56,絕大部分uNK細胞表型為CD(56bright)CD16(-),細胞毒性低,分泌免疫調(diào)節(jié)細胞因子、血管生長因子等,在著床和蛻膜免疫調(diào)節(jié)中發(fā)揮積極功能作用。反復(fù)種植失敗患者分泌期CD56+細胞比率高于正常婦女,提示uNK細胞可能在反復(fù)種植失敗中對子宮內(nèi)膜容受性的調(diào)節(jié)起到一定作用。白細胞介素-15(interleukelin-15,IL-15)是屬于Th1相關(guān)性細胞因子,有研究顯示它能促進NK細胞的分化和功能作用,正常婦女子宮內(nèi)膜分泌期IL-15 mRNA表達上調(diào),在分泌晚期升高為胚胎著床做好準備。IL-15是否在反復(fù)種植失敗的患者分泌期內(nèi)膜的表達增加,需要作進一步研究。有研究提示當(dāng)腫瘤壞死因子-α(tumour necrosis factor-α,TNF-α)表達過高時,打破了種植窗Th1/Th2因子的平衡,抑制子宮內(nèi)膜蛻膜化進程,促使上皮細胞凋亡,增加Th1型細胞因子的免疫殺傷反應(yīng),阻斷滋養(yǎng)細胞的侵入,產(chǎn)生前列腺素和活化金屬蛋白酶(MMPs)如MMP-2和MMP-9,降解絨毛的細胞外基質(zhì),引發(fā)早期妊娠失敗。因此,uNK細胞與胚胎種植、胎兒生長發(fā)育和早期胎盤密切相關(guān),這種關(guān)系一旦失去平衡,就會引起反復(fù)種植失敗或早期自然流產(chǎn)。在各種打破免疫因素平衡的改變可能導(dǎo)致胚胎著床失敗,因此本研究檢測RIF子宮內(nèi)膜CD56、IL-15、TNF-α的表達改變,探索其與RIF發(fā)生的相關(guān)性。目的1.分別檢測RIF與正常分泌期子宮內(nèi)膜CD56、IL-15、TNF-α的表達情況。2.探索CD56、IL-15、TNF-α在RIF患者子宮內(nèi)膜分泌期是否表達相關(guān),為RIF患者的臨床治療提供理論依據(jù)。材料與方法本研究課題經(jīng)過鄭州大學(xué)第一附屬醫(yī)院的倫理委員會批準,研究中所有入組研究對象均已告知實驗內(nèi)容并已簽署知情同意書。選擇2016年9月至2017年3月于本院生殖中心行IVF-ET/ICSI-ET/Thaw-ET助孕的患者中有助孕妊娠史擬再次助孕者為對照組,以至少移植4個優(yōu)質(zhì)胚胎或至少移植三個新鮮周期或冷凍周期后仍未能實現(xiàn)臨床妊娠的患者為實驗組。本實驗分為兩個部分,第一部分實驗包括10例對照組和12例實驗組,用qRT-PCR法檢測子宮內(nèi)膜CD56、IL-15、TNF-α的定量表達;第二部分實驗包括10例對照組和12例實驗組,用免疫組化法檢測子宮內(nèi)膜CD56、IL-15、TNF-α的定位表達。結(jié)果1.qRT-PCR法檢測結(jié)果顯示,CD56、IL-15、TNF-α在分泌期正常子宮內(nèi)膜與反復(fù)種植失敗患者內(nèi)膜均有表達,但在RIF組表達均顯著高于對照組,差異有顯著統(tǒng)計學(xué)差異(CD56:4.533±2.616vs.1.302±1.163,P=0.002;IL-15:4.064±2.247vs.1.614±1.713,P=0.01;TNF-α:6.313±1.912vs.1.479±0.986,P=0.000)。2.免疫組化結(jié)果顯示,CD56、IL-15、TNF-α在分泌期正常子宮內(nèi)膜與反復(fù)種植失敗患者子宮內(nèi)膜腺上皮與基質(zhì)細胞中均有表達,RIF組的平均光密度值顯著高于對照組,差異有統(tǒng)計學(xué)意義(P0.05)。3.CD56的表達升高對RIF的診斷效能高,且與IL-15和TNF-α的表達均呈正相關(guān)(P0.05)。結(jié)論1.CD56、IL-15、TNF-α在反復(fù)種植失敗分泌期子宮內(nèi)膜比正常內(nèi)膜表達均升高。2.CD56的表達升高對RIF有診斷價值,且與IL-15和TNF-α的表達可能存在一定聯(lián)系,需進一步研究證實。
[Abstract]:The research background of repeated implantation failure (repeated implant failure, RIF) the specific molecular mechanism is not very clear, it is known that 2/3 RIF is caused by the imbalance of endometrial receptivity, the reason may be related to immune related immunological studies have indicated that pregnancy is an allograft rejection and normal pregnancy embryos. Half body tissue antigen by maternal rejection and survival, have a certain relationship with decidual tissue and normal immune microenvironment. Uterine natural killer cells (uterine natural killer cell, uNK) is a unique natural killer (NK) endometrial cells, surface specific marker is CD56, most of the uNK cell phenotype was CD (56bright) CD16 (-), low cytotoxicity, secretion of immunomodulatory cytokines, vascular endothelial growth factor, play a positive role in the function of implantation and decidual immune regulation. CD56+ secretion in patients with repeated implantation failure The percentage of cells was higher than that of normal women, suggesting that uNK cells may be repeated implantation failure to a certain role in the regulation of endometrial receptivity. Interleukin -15 (interleukelin-15, IL-15) belongs to Th1 related cytokines, studies have shown that it can promote the differentiation and function of NK cells, upregulation of the expression of IL-15 mRNA the normal endometrial secretion in late secretory increased expression of.IL-15 is good for embryo implantation in secretory endometrium in repeated implantation failure in patients with increased need for further research. Some studies suggest that when the tumor necrosis factor alpha (tumour alpha factor- alpha necrosis, TNF-) expression is too high, breaking the window of the implantation of Th1/Th2 factor the balance of inhibition of endometrial decidualization process, promote epithelial cell apoptosis, increase immune Th1 cytokine killing response, blocking the invasion of trophoblast cells, produce prostaglandin And the activation of metalloproteinases (MMPs) such as MMP-2 and MMP-9, the degradation of extracellular matrix of the villi, causing early pregnancy failure. Therefore, uNK cells and embryo implantation, fetal growth and early placenta are closely related, once the relationship is out of balance, it will cause repeated implantation failure or early spontaneous abortion. Break the immune factors of the change of the balance in may lead to embryo implantation failure, therefore the detection of endometrial RIF CD56, IL-15, change the expression of TNF- and explore its correlation with the occurrence of RIF. 1. RIF were detected with normal secretory phase endometrial CD56, IL-15, TNF- alpha.2. expression to explore CD56, IL-15, whether the period of expression secretion of TNF- in endometrium of patients with RIF, and provide a theoretical basis for the clinical treatment of RIF patients. The research materials and methods after the First Affiliated Hospital of Zhengzhou University ethics committee approved the study. All subjects were informed of experimental content and signed informed consent. From September 2016 to March 2017 in our hospital reproductive center IVF-ET/ICSI-ET/Thaw-ET help pregnant patients with pregnancy pregnancy history to help pregnant again for the control group, with at least 4 high-quality embryo transplantation Transplantation or at least three fresh or frozen cycle cycle after failed to achieve clinical pregnancy patients as the experimental group. The experiment is divided into two parts, the first part of the experiment including 10 cases in the control group and 12 cases in the experimental group, qRT-PCR was used to detect endometrial CD56, IL-15, quantitative expression of TNF- alpha; the second part of the experiment including 10 cases in the control group and 12 patients in the experimental group. The method of detection of endometrial CD56, with immuno IL-15, expression of TNF- alpha. The results of 1.qRT-PCR assay showed that CD56, IL-15, TNF- alpha in the secretory phase of normal endometrium and repeated implantation failure in patients with membrane were The expression, but the expression in RIF group were significantly higher than control group, there was significant difference statistically (CD56:4.533 + 2.616vs.1.302 + 1.163, P=0.002 + 2.247vs.1.614 + 1.713; IL-15:4.064, P=0.01; TNF-: alpha 6.313 + 1.912vs.1.479 + 0.986, P=0.000).2. immunohistochemistry results showed that CD56, IL-15, TNF- alpha in the secretory phase of normal uterus endometrial and repeated implantation failure were expressed in patients with endometrial epithelial and stromal cells, the average optical density of RIF group was significantly higher than the control group, the difference was statistically significant (P0.05) the increased expression of.3.CD56 on RIF expression and diagnosis efficiency is high, and IL-15 and TNF- alpha were positively correlated (P0.05) conclusion. 1.CD56, IL-15, TNF- alpha in repeated implantation failure in secretory endometrium than normal endometrial expression and increased the expression of.2.CD56 in diagnosing RIF, and the expression of IL-15 and TNF- and alpha may be related to the need to further research. This confirmed.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R714.8

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