TLR2和TLR4的表達與自然流產(chǎn)的相關(guān)性研究
發(fā)布時間：2018-09-15 20:09
【摘要】：目的:流產(chǎn)(Abortion)是指懷孕未滿28周、胎兒體重未滿1000g而使懷孕受到終止,早期流產(chǎn)是指發(fā)生在懷孕12周以前者,晚期流產(chǎn)是指發(fā)生在滿12周及其之后者。自然流產(chǎn)是早孕期間比較多見的病癥,其發(fā)病原因和機制十分繁雜,除去常見的解剖結(jié)構(gòu)異常(如子宮畸形、宮頸功能不全等)、染色體異常、遺傳、內(nèi)分泌、理化環(huán)境及感染等因素外,近年來生殖免疫成為研究熱點之一,也有相關(guān)研究表明了免疫因素與自然流產(chǎn)密切相關(guān)。該理論認為,從免疫移植學(xué)角度而言,之所以懷孕期間孕囊作為帶有“外來”抗原的同種異體移植物可以存在于母親體內(nèi),是因為母體胎兒面免疫系統(tǒng)的精細和復(fù)雜的調(diào)節(jié)。很多因素可以經(jīng)過活化母親體內(nèi)Toll樣受體(Toll like receptors,TLRs),改變母體胎兒面多種活性因子的分布水平,破壞了母體胎兒面的免疫均衡,使得孕囊被母親體內(nèi)的免疫反應(yīng)所排斥,引發(fā)流產(chǎn)。TLRs是一類能辨識病原微生物的模式分子,有調(diào)控天然免疫和獲得性免疫的作用,并且參與母體胎兒面的抗病原微生物的天然免疫應(yīng)答,TLRs既表達在免疫活性細胞,也在其他部位表達,如絨毛滋養(yǎng)細胞、蛻膜組織等,在維系健康妊娠和自然流產(chǎn)發(fā)病中起到不可忽視的作用。目前關(guān)于與妊娠流產(chǎn)的相關(guān)TLRs中,對Toll樣受體2和4的研究相對較多,它們是體內(nèi)非常關(guān)鍵的自然免疫蛋白,也是TLRs家族亞類特征性的兩個,在大部分細胞系的細胞膜上都有分布,骨髓中單核細胞分布最多,在中性粒細胞、巨噬細胞、樹突狀細胞等細胞膜上也分布較多,另外,還分布于心肌細胞、微血管內(nèi)皮細胞、氣道上皮細胞、脂肪細胞、消化道上皮細胞、人胚胎腎細胞、齒齦纖維母細胞、人表皮和臍靜脈內(nèi)皮細胞以及胎盤滋養(yǎng)細胞[1]。Toll樣受體2辨識肽聚糖,Toll樣受體4辨識脂多糖、內(nèi)毒素等,經(jīng)過髓樣分化蛋白88(MyD88)依賴性和非依賴性反應(yīng)轉(zhuǎn)導(dǎo)路徑引起母體胎兒面的免疫活性因子Th1/Th2失去平衡。Th1分泌的趨化因子產(chǎn)生過多,對滋養(yǎng)層細胞產(chǎn)生細胞毒性作用而形成免疫損傷,直接或間接影響孕囊的著床和成長發(fā)育,而Th2則起到了維持母體胎兒面的免疫保護作用。故而,當Th1/Th2偏向Th1時發(fā)生病理性懷孕的風(fēng)險增加。如果對自然流產(chǎn)的患者盲目給予保胎,而不是對因治療,往往達不到醫(yī)生和患者所期待的效果。因此盡最大可能進行分析和尋找病因變的重要之至。文章就Toll樣受體2和4在絨毛和外周血中的分布情況與自然流產(chǎn)的相關(guān)性進行探索。方法:選擇2014年06月-2014年12月在解放軍第105醫(yī)院婦產(chǎn)科門診患者(年齡35歲、孕周12周)作為本次實驗的研究對象:本次懷孕結(jié)局為自然流產(chǎn)者、因意外懷孕自愿行人流終止妊娠的健康的早孕婦女。納入的研究對象均由�？漆t(yī)師對病史進行問詢,包括既往史、月經(jīng)史、婚育史、家族史等,并核實填寫項目是否真實、準確。體格檢查包括:一般體格檢查:血壓、身高、體重、甲狀腺、乳腺等,及常規(guī)婦科檢查。所有對象均接受基礎(chǔ)性激素檢查、b超檢查、夫婦染色體檢查、有無急慢性傳染病、婦科炎癥及與懷孕相關(guān)聯(lián)的免疫抗體(如抗磷脂抗體、抗β2糖蛋白抗體、抗核抗體、抗甲狀腺抗體、狼瘡抗凝血因子等為陽性者)等輔助檢查,盡可能排除遺傳、染色體、解剖等相關(guān)因素。本次懷孕結(jié)局為自然流產(chǎn)患者列為研究組;將曾有懷孕和生育史,本次因意外懷孕自愿行人流終止妊娠的健康孕婦列為對照組,每組各20例。采用免疫組化法檢查每例患者絨毛滋養(yǎng)細胞中toll樣受體2和4的分布水平(每個樣本隨機抽選一張切片,以觀察絨毛滋養(yǎng)細胞胞漿內(nèi)是否含有棕黃色顆粒為判斷標準)。采用spss17.0統(tǒng)計軟件進行分析處理。用平均值加減標準差分析。若p0.05,則有統(tǒng)計學(xué)差異;采用流式細胞儀檢測tlr2和tlr4分別在外周血淋巴細胞群、單核細胞群和粒細胞群的分布比值進行分析。結(jié)果:1、自然流產(chǎn)組與妊娠對照組之間的年齡、孕齡和孕次的差異等均無統(tǒng)計學(xué)意義。2、tlr2和tlr4在自然流產(chǎn)組和妊娠對照組的絨毛滋養(yǎng)細胞均見分布,主要分布在合體滋養(yǎng)細胞的胞漿中。3、tlr2在自然流產(chǎn)組和妊娠對照組的絨毛、外周血中單核細胞群和粒細胞群的分布水平差異無統(tǒng)計學(xué)意義(p0.05),tlr2在自然流產(chǎn)組和妊娠對照組的外周血中淋巴細胞群的分布水平差異具有統(tǒng)計學(xué)意義(p0.05)。4、自然流產(chǎn)組和妊娠對照組相比,tlr4在兩組絨毛及外周血淋巴細胞群、單核細胞群和粒細胞群的分布水平差異有統(tǒng)計學(xué)意義(p0.05)。結(jié)論:1.tlr2和tlr4在自然流產(chǎn)組和妊娠對照組絨毛滋養(yǎng)細胞、外周血淋巴細胞群、單核細胞群和粒細胞群中都有表達。2.tlr2在自然流產(chǎn)組外周血中淋巴細胞群的表達明顯升高,tlr4在自然流產(chǎn)組絨毛滋養(yǎng)細胞的表達明顯上調(diào)。3.tlr4在自然流產(chǎn)組絨毛組織、外周血中淋巴細胞群、單核細胞群和粒細胞群中的分布均升高明顯。通過對早孕期婦女進行外周血的tlr2和tlr4的檢測,有利于預(yù)測孕婦可能發(fā)生的自然流產(chǎn)的風(fēng)險,以期預(yù)防或干預(yù),降低流產(chǎn)的發(fā)生率。
[Abstract]:Objective: Abortion refers to the termination of pregnancy before 28 weeks of gestation and under 1000g of fetal weight. Early abortion refers to those who occur before 12 weeks of gestation. Late abortion refers to those who occur after 12 weeks of gestation. In recent years, reproductive immunity has become one of the hotspots of research, and some related studies have shown that immune factors are closely related to spontaneous abortion. During this period, gestational sac, as an allograft with "foreign" antigen, can exist in the mother because of the fine and complicated regulation of the maternal fetal immune system. TLRs are a kind of model molecule which can identify pathogenic microorganisms, regulate innate immunity and acquired immunity, and participate in the innate immune response against pathogenic microorganisms on the maternal and fetal surfaces. TLRs are expressed in immune activity. Sex cells, also expressed in other parts of the body, such as choriotrophoblasts and decidual tissue, play an important role in maintaining healthy pregnancy and spontaneous abortion. Two characteristic subclasses are distributed on the cell membranes of most cell lines. Monocytes are most distributed in bone marrow. They are also distributed on the cell membranes of neutrophils, macrophages, dendritic cells and so on. In addition, they are also distributed in cardiomyocytes, microvascular endothelial cells, airway epithelial cells, adipocytes, gastrointestinal epithelial cells, and human beings. Embryonic kidney cells, gingival fibroblasts, human epidermal and umbilical vein endothelial cells and placental trophoblasts [1]. Toll-like receptor 2 recognizing peptidoglycans, Toll-like receptor 4 recognizing lipopolysaccharides, endotoxins, etc., through myeloid differentiation protein 88 (MyD88) dependent and independent response transduction pathways cause the loss of maternal and fetal immune activity factor Th1/Th2. Th1 produces too many chemokines, which produce cytotoxic effects on trophoblast cells and cause immune damage, directly or indirectly affecting implantation and growth of gestational sacs, while Th2 protects the immune function of maintaining maternal and fetal surface. Therefore, the risk of pathological pregnancy increases when Th1/Th2 is biased towards Th1. The distribution of Toll-like receptors 2 and 4 in villi and peripheral blood and the relationship between the distribution of Toll-like receptors 2 and 4 in villi and peripheral blood and spontaneous abortion were explored. From June 14 to December 2014, patients aged 35 and 12 weeks of gestation in the outpatient department of gynecology and obstetrics of the 105th Hospital of the PLA were selected as the subjects of this study. Physical examinations include general physical examinations: blood pressure, height, weight, thyroid gland, breast gland, and routine gynecological examinations. All subjects were examined for basic sex hormones, ultrasound, couple chromosomes, acute and chronic infectious diseases, gynecological inflammation. The pregnant women with spontaneous abortion were enrolled in the study group. The pregnant women with previous pregnancy and childbearing history were enrolled in the study group. The distribution of Toll-like receptors 2 and 4 in trophoblastic cells of each patient was examined by immunohistochemistry. A section was randomly selected from each sample to observe whether there were brown granules in cytoplasm of trophoblastic cells. SPSS 17.0 statistical software was used for analysis and processing.The standard deviation analysis was used for average addition and subtraction.If p0.05, there was statistical difference.Flow cytometry was used to detect the distribution ratio of TLR2 and TLR4 in peripheral blood lymphocyte population, monocyte population and granulocyte population respectively.Results:1. Natural abortion group and pregnancy control group. TLR2 and TLR4 were distributed in the cytoplasm of syncytiotrophoblast. 3. the distribution of TLR2 in the villi of spontaneous abortion group and pregnancy control group was different. There was no significant difference between the two groups (p0.05). The distribution of TLR2 in peripheral blood lymphocyte group was significantly different between the spontaneous abortion group and the pregnancy control group (p0.05). 4. Compared with the pregnancy control group, the distribution of TLR4 in villi and peripheral blood lymphocyte group, monocyte group and granulocyte group were statistically different between the two groups. Conclusion: 1. The expression of TLR2 and TLR4 in choriotrophoblasts, peripheral blood lymphocyte, monocyte and granulocyte in spontaneous abortion group and pregnancy control group were significantly increased. 2. The expression of TLR2 in peripheral blood lymphocyte was significantly increased in spontaneous abortion group, and the expression of TLR4 in choriotrophocyte in spontaneous abortion group was significantly increased. The distribution of TLR4 in villi, peripheral blood lymphocyte, monocyte and granulocyte increased significantly in spontaneous abortion group. The detection of TLR2 and TLR4 in peripheral blood of early pregnant women is helpful to predict the risk of spontaneous abortion in order to prevent or intervene and reduce the incidence of abortion.
【學(xué)位授予單位】：蚌埠醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R714.21
本文編號：2244381
[Abstract]:Objective: Abortion refers to the termination of pregnancy before 28 weeks of gestation and under 1000g of fetal weight. Early abortion refers to those who occur before 12 weeks of gestation. Late abortion refers to those who occur after 12 weeks of gestation. In recent years, reproductive immunity has become one of the hotspots of research, and some related studies have shown that immune factors are closely related to spontaneous abortion. During this period, gestational sac, as an allograft with "foreign" antigen, can exist in the mother because of the fine and complicated regulation of the maternal fetal immune system. TLRs are a kind of model molecule which can identify pathogenic microorganisms, regulate innate immunity and acquired immunity, and participate in the innate immune response against pathogenic microorganisms on the maternal and fetal surfaces. TLRs are expressed in immune activity. Sex cells, also expressed in other parts of the body, such as choriotrophoblasts and decidual tissue, play an important role in maintaining healthy pregnancy and spontaneous abortion. Two characteristic subclasses are distributed on the cell membranes of most cell lines. Monocytes are most distributed in bone marrow. They are also distributed on the cell membranes of neutrophils, macrophages, dendritic cells and so on. In addition, they are also distributed in cardiomyocytes, microvascular endothelial cells, airway epithelial cells, adipocytes, gastrointestinal epithelial cells, and human beings. Embryonic kidney cells, gingival fibroblasts, human epidermal and umbilical vein endothelial cells and placental trophoblasts [1]. Toll-like receptor 2 recognizing peptidoglycans, Toll-like receptor 4 recognizing lipopolysaccharides, endotoxins, etc., through myeloid differentiation protein 88 (MyD88) dependent and independent response transduction pathways cause the loss of maternal and fetal immune activity factor Th1/Th2. Th1 produces too many chemokines, which produce cytotoxic effects on trophoblast cells and cause immune damage, directly or indirectly affecting implantation and growth of gestational sacs, while Th2 protects the immune function of maintaining maternal and fetal surface. Therefore, the risk of pathological pregnancy increases when Th1/Th2 is biased towards Th1. The distribution of Toll-like receptors 2 and 4 in villi and peripheral blood and the relationship between the distribution of Toll-like receptors 2 and 4 in villi and peripheral blood and spontaneous abortion were explored. From June 14 to December 2014, patients aged 35 and 12 weeks of gestation in the outpatient department of gynecology and obstetrics of the 105th Hospital of the PLA were selected as the subjects of this study. Physical examinations include general physical examinations: blood pressure, height, weight, thyroid gland, breast gland, and routine gynecological examinations. All subjects were examined for basic sex hormones, ultrasound, couple chromosomes, acute and chronic infectious diseases, gynecological inflammation. The pregnant women with spontaneous abortion were enrolled in the study group. The pregnant women with previous pregnancy and childbearing history were enrolled in the study group. The distribution of Toll-like receptors 2 and 4 in trophoblastic cells of each patient was examined by immunohistochemistry. A section was randomly selected from each sample to observe whether there were brown granules in cytoplasm of trophoblastic cells. SPSS 17.0 statistical software was used for analysis and processing.The standard deviation analysis was used for average addition and subtraction.If p0.05, there was statistical difference.Flow cytometry was used to detect the distribution ratio of TLR2 and TLR4 in peripheral blood lymphocyte population, monocyte population and granulocyte population respectively.Results:1. Natural abortion group and pregnancy control group. TLR2 and TLR4 were distributed in the cytoplasm of syncytiotrophoblast. 3. the distribution of TLR2 in the villi of spontaneous abortion group and pregnancy control group was different. There was no significant difference between the two groups (p0.05). The distribution of TLR2 in peripheral blood lymphocyte group was significantly different between the spontaneous abortion group and the pregnancy control group (p0.05). 4. Compared with the pregnancy control group, the distribution of TLR4 in villi and peripheral blood lymphocyte group, monocyte group and granulocyte group were statistically different between the two groups. Conclusion: 1. The expression of TLR2 and TLR4 in choriotrophoblasts, peripheral blood lymphocyte, monocyte and granulocyte in spontaneous abortion group and pregnancy control group were significantly increased. 2. The expression of TLR2 in peripheral blood lymphocyte was significantly increased in spontaneous abortion group, and the expression of TLR4 in choriotrophocyte in spontaneous abortion group was significantly increased. The distribution of TLR4 in villi, peripheral blood lymphocyte, monocyte and granulocyte increased significantly in spontaneous abortion group. The detection of TLR2 and TLR4 in peripheral blood of early pregnant women is helpful to predict the risk of spontaneous abortion in order to prevent or intervene and reduce the incidence of abortion.
【學(xué)位授予單位】：蚌埠醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R714.21
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