【摘要】：妊娠是一個獨特的免疫學事件。妊娠成功需要通過精細的母-胎對話,在母-胎界面建立獨特的免疫耐受微環(huán)境。母-胎界面多種細胞和分子之間的對話是母-胎調(diào)節(jié)的核心內(nèi)容,解析其中的免疫細胞,滋養(yǎng)細胞和蛻膜基質(zhì)細胞通過它們表面膜分子和分泌的細胞因子之間的相互作用,是闡明母-胎免疫耐受機制的重要研究內(nèi)容,不僅對生殖免疫學,而且對腫瘤和移植免疫學都具有重要的理論和臨床意義。白細胞相關免疫球蛋白樣受體(LAIR)是新近鑒定的以膠原為配體的免疫受體。LAIR-1廣泛表達在造血細胞和各類免疫細胞表面,胞質(zhì)區(qū)有ITIM基序,LAIR-1對外周血免疫細胞功能的調(diào)節(jié)作用及其在腫瘤免疫和移植免疫中的意義是免疫學研究的熱點。然而,在生殖免疫學中,目前還沒有任何相關研究。膠原蛋白作為母-胎界面含量豐富的重要細胞外基質(zhì),在妊娠維持以及免疫調(diào)節(jié)中的作用研究也甚少。蛻膜NK細胞約占蛻膜免疫細胞總數(shù)的70%,其表型和生物學行為對母-胎免疫耐受的形成發(fā)揮著至關重要的作用。本研究在分析了LAIRs和膠原分子在母-胎界面的表達及其和自然流產(chǎn)關系的基礎上,從LAIR-1和膠原分子的相互作用對在母-胎界面占絕對組成優(yōu)勢的早孕期NK細胞的調(diào)控入手,以解析滋養(yǎng)細胞和蛻膜基質(zhì)細胞通過表達的膠原蛋白和LAIRs的相互作用對NK細胞表型和生物學行為的調(diào)節(jié),并進一步研究JAK-STAT信號通路在此調(diào)節(jié)中的角色。研究成果可以為臨床上全面理解自然流產(chǎn)等母-胎免疫調(diào)節(jié)紊亂性疾病提供新的視角,同時對相關疾病的診斷和防治也可提供新的靶點和思路。第一部分LAIR-1和膠原分子的表達水平與自然流產(chǎn)相關目的分析比較LAIR家族成員(LAIRs)和膠原分子在正常和異常妊娠組織中的表達；以及在體外培養(yǎng)的正常和流產(chǎn)的滋養(yǎng)細胞,蛻膜基質(zhì)細胞和NK細胞中的表達。方法收集正常和異常妊娠早孕期婦女的絨毛和蛻膜組織,采用馬松染色法(Masson)和免疫組化技術(shù)(IH)分析LAIR-1和膠原分子在其中的表達情況；分離各種早孕期滋養(yǎng)細胞,蛻膜基質(zhì)細胞(DSC)和蛻膜免疫細胞(DIC),采用多聚酶鏈式反應(PCR),酶聯(lián)免疫吸附(ELISA)等技術(shù)分析以上細胞中多種LAIRs和膠原分子表達的情況；用流式細胞術(shù)(FCM)分析正常和流產(chǎn)組織蛻膜NK細胞LAIR-1的表達。結(jié)果獲得了較全面的LAIRs和膠原分子在正常妊娠和自然流產(chǎn)組織中的表達情況。對比分析結(jié)果顯示：正常妊娠的絨毛和蛻膜組織相對于自然流產(chǎn)的絨毛和蛻膜組織,都有更高水平膠原的表達；體外培養(yǎng)的正常滋養(yǎng)細胞、蛻膜基質(zhì)細胞在mRNA和蛋白水平也都比自然流產(chǎn)的滋養(yǎng)細胞、蛻膜基質(zhì)細胞表達分泌更高水平的膠原蛋白；正常妊娠的蛻膜組織比自然流產(chǎn)的蛻膜組織表達更高的LAIR-1,并且正常妊娠的蛻膜NK也比自然流產(chǎn)的蛻膜NK細胞表達更高水平的LAIR-1。結(jié)論 人早孕期母-胎界面滋養(yǎng)細胞和蛻膜基質(zhì)細胞的膠原蛋白表達下降和自然流產(chǎn)具有相關性；蛻膜組織和蛻膜NK細胞LAIR-1的低表達與自然流產(chǎn)也有相關性。第二部分LAIRs和膠原分子相互作用調(diào)節(jié)NK細胞表型目的解析LAIR-1和膠原分子相互作用的特點,及其對外周NK細胞及蛻膜NK細胞表面受體和細胞內(nèi)細胞因子表達的調(diào)節(jié)作用。方法常規(guī)無菌分離外周血單個核細胞(PBMC)和蛻膜免疫細胞(DIC)后,磁珠分選其中的外周NK細胞和蛻膜NK細胞,并在其體外培養(yǎng)體系中加入不同濃度的膠原分子,用多聚酶鏈式反應(PCR)和流式細胞(FCM)技術(shù)分析膠原分子受體LAIR-1的表達情況；進一步在早孕期NK細胞培養(yǎng)體系加入膠原蛋白分子,并且設立LAIR-2處理組,用FCM分析NK細胞表面的激活性受體和抑制性受體以及細胞內(nèi)Thl、Th2型細胞因子和殺傷活性相關分子的表達。結(jié)果 膠原蛋白分子可以劑量依賴性的方式誘導其受體LAIR-1在NK細胞mRNA和蛋白水平表達增加。膠原蛋白分子可以通過和LAIR-1的相互作用降低蛻膜NK細胞表面激活性受體NKp30的表達,上調(diào)抑制性受體KIR2DL1的表達；膠原蛋白分子和LAIR-1的相互作用也可以降低蛻膜NK細胞Thl型細胞因子IFN-γ口TNF-a的表達,而不影響蛻膜NK細胞Th2型細胞因子IL-4和IL-10的表達；高濃度膠原蛋白分子可以降低蛻膜NK細胞穿孔素的表達,且后者的表達和]LAIR-1表達的熒光強度成反比,這種作用以及膠原蛋白分子對NK細胞表型和Thl型細胞因子表達的調(diào)節(jié)都可以被LAIR-2所拮抗。結(jié)論膠原分子上調(diào)NK細胞中LAIR-1的表達,并且通過和LAIR-1的相互作用可以降低NK細胞Th1型細胞因子和穿孔素的表達,誘導蛻膜NK細胞的耐受表型。第三部分 滋養(yǎng)細胞和蛻膜基質(zhì)細胞通過膠原分子參與調(diào)節(jié)蛻膜NK細胞的功能目的解析人早孕期母-胎界面的滋養(yǎng)細胞和蛻膜基質(zhì)細胞通過表達的膠原蛋白分子對蛻膜NK細胞表型的調(diào)節(jié)作用。方法在體外建立人早孕期滋養(yǎng)細胞,蛻膜基質(zhì)細胞單獨培養(yǎng)、以及滋養(yǎng)細胞和蛻膜基質(zhì)細胞共培養(yǎng)體系來模擬早孕期母-胎界面微環(huán)境,然后與純化的蛻膜NK細胞共培養(yǎng),并設立LAIR-2處理組,用流式細胞術(shù)(FCM)分析蛻膜NK細胞的表面激活性受體和抑制性受體以及細胞內(nèi)細胞因子和殺傷活性相關分子的表達。進一步用P4H shRNA質(zhì)粒轉(zhuǎn)染滋養(yǎng)細胞與蛻膜基質(zhì)細胞來模擬自然流產(chǎn)的母-胎界面膠原蛋白分子低水平表達的微環(huán)境,用多聚酶鏈式反應(PCR)、酶聯(lián)免疫吸附(ELISA)方法和氨基酸分析儀檢測轉(zhuǎn)染處理后,滋養(yǎng)細胞、蛻膜基質(zhì)細胞單獨培養(yǎng)和共培養(yǎng)體系中膠原蛋白的表達水平；然后用FCM分析蛻膜NK細胞表面的激活性受體和抑制性受體以及細胞內(nèi)細胞因子和殺傷活性相關分子的表達。結(jié)果滋養(yǎng)細胞和蛻膜基質(zhì)細胞可以通過分泌膠原分子與LAIR-1相互作用降低蛻膜NK細胞表面激活性受體NKp30的表達,上調(diào)抑制性受體KIR2DL1的表達；也可以降低蛻膜NK細胞Thl型細胞因子IFN-y和]TNF-a,以及穿孔素的表達。用LAIR-2阻斷和P4H shRNA質(zhì)粒轉(zhuǎn)染以基因沉默膠原合成,都能夠抑制滋養(yǎng)細胞與蛻膜基質(zhì)細胞對蛻膜NK細胞的表面受體、細胞內(nèi)細胞因子以及殺傷活性的調(diào)節(jié)作用。值得一提的是,用P4H shRNA質(zhì)粒轉(zhuǎn)染滋養(yǎng)細胞與蛻膜基質(zhì)細胞會使蛻膜NK細胞Th2型細胞因子IL-4和IL-10的表達水平下降。結(jié)論人早孕期滋養(yǎng)細胞和蛻膜基質(zhì)細胞可以通過表達的膠原分子參與調(diào)節(jié)蛻膜NK細胞的功能,從而有利于正常妊娠的維持。第四部分JAK-STAT信號通路參與LAIR-1對NK細胞的調(diào)節(jié)作用目的解析LAIR-1調(diào)節(jié)NK細胞功能的信號通路。方法在純化的外周NK細胞(pNK)和蛻膜NK細胞(dNK)的體外培養(yǎng)體系中加入膠原蛋白分子；用shRNA轉(zhuǎn)染的滋養(yǎng)細胞和蛻膜基質(zhì)細胞共培養(yǎng)的上清(Culture Medium, CM)培養(yǎng)NK細胞后,用免疫蛋白印跡實驗(Western Blot)分析LAIR-1和AK-STAT信號通路中STAT1、p-STAT1、STAT4、p-STAT4的表達,進一步用Western Blot和流式細胞術(shù)(FCM)分析JAK-STAT信號通路下游相關轉(zhuǎn)錄因子T-bet和Helios等的表達；用免疫共沉淀技術(shù)(CoIP)分析JAK-STAT信號通路上游相關分子JAK1、JAK2和SHP-1的相互關系,以及SHP-1和LAIR-1的相互作用關系。用病毒質(zhì)粒構(gòu)建LAIR-1過表達的穩(wěn)轉(zhuǎn)細胞株NK-92-LAIR-1,并且通過QPCR、Western Blot和熒光顯微鏡進行鑒定,進一步對其在活化狀態(tài)下STATs和LAIR-1的表達進行初步分析。結(jié)果在膠原蛋白分子的刺激下,LAIR-1可以募集SHP-1,并通過后者和JAK1、JAK2的直接作用,對JAK-STAT信號通路中STAT1、STAT4的活化發(fā)揮抑制作用,進而影響轉(zhuǎn)錄因子T-bet和Helios等的表達；成功地構(gòu)建了LAIR-1過表達的穩(wěn)轉(zhuǎn)細胞株NK-92-LAIR-1.結(jié)論JAK-STAT信號通路參與LAIR-1和膠原分子相互作用對NK細胞的調(diào)節(jié)作用。LAIR-1過表達穩(wěn)轉(zhuǎn)細胞株的建立為我們后期進行深入系統(tǒng)的相關研究工作打下了堅實的基礎。
[Abstract]:Pregnancy is a unique immunological event. Pregnancy success requires a delicate mother fetal dialogue to establish a unique immune tolerance microenvironment at the mother fetal interface. The dialogue between cells and molecules at the mother fetal interface is the core of the maternal fetal regulation, parsing the immune cells, trophoblastic cells and decidual stromal cells through their tables. The interaction between the mask molecules and the secreted cytokine is an important study of the mechanism of maternal fetal immune tolerance, not only for reproductive immunology, but also of important theoretical and clinical significance for both tumor and transplantation immunology. The leukocyte related immunoglobulin like receptor (LAIR) is a newly identified collagen free ligand. The pestilence receptor.LAIR-1 is widely expressed in the surface of hematopoietic cells and various immune cells, the cytoplasmic region has ITIM motif, the role of LAIR-1 in the immunological function of peripheral blood and its significance in the immunology and transplantation of the tumor are the hot spots of immunology. However, there is no related research in the reproductive immunology. The role of an important extracellular matrix, rich in maternal fetal interface, is rarely studied in pregnancy maintenance and immunoregulation. Decidua NK cells account for about 70% of the total number of decidual immune cells. Their phenotypic and biological behavior plays a vital role in the formation of maternal fetal immune tolerance. This study analyzed the LAIRs and collagen molecules in this study. On the basis of the relationship between mother fetal interface and spontaneous abortion, the interaction between LAIR-1 and collagen molecules begins with the regulation of the early pregnancy NK cells with the absolute dominance of the mother fetal interface, in order to analyze the phenotype and biology of the trophoblast and the decidual stromal cells through the interaction of the collagen and LAIRs expressed by the NK cells. Regulation of behavior and further study of the role of JAK-STAT signaling in this regulation. The results can provide a new perspective for a comprehensive understanding of maternal fetal immunomodulatory disorders, such as spontaneous abortion, and also provide new targets and ideas for the diagnosis and prevention of related diseases. Part 1, LAIR-1 and collagen molecules Expressions of LAIR family members (LAIRs) and collagen molecules in normal and abnormal pregnancy tissues, and the expression of normal and abortive trophoblastic cells, decidual stromal cells and NK cells in vitro. Methods to collect the villus and decidua of normal and abnormal pregnancy women. Tissue, the expression of LAIR-1 and collagen molecules were analyzed by Masson staining (Masson) and immunohistochemical technique (IH), and various early pregnancy trophoblastic cells, decidual stromal cells (DSC) and decidual immune cells (DIC), polymerase chain reaction (PCR) and enzyme linked immunosorbent assay (ELISA) were used to analyze a variety of LAIRs in the above cells. The expression of collagen molecules and the expression of LAIR-1 in normal and aborted tissue decidua NK cells by flow cytometry (FCM). Results obtained more comprehensive expression of LAIRs and collagen molecules in normal pregnancy and spontaneous abortion tissues. Comparative analysis showed that the villus and decidua tissues of normal pregnancy were relative to spontaneous abortion. The villi and decidual tissues all have higher level of collagen expression; in vitro cultured normal trophoblastic cells, decidual stromal cells also express higher levels of collagen than spontaneous abortion trophoblastic cells and decidual stromal cells, and the decidual tissue of normal pregnancy is more expressive than natural abortion decidual tissue. High LAIR-1, and the decidual NK in normal pregnancy also expressed higher levels of LAIR-1. than decidual NK cells in spontaneous abortion. Conclusion the decrease of collagen expression in mother fetal interface trophoblast and decidual stromal cells in early pregnancy was associated with spontaneous abortion, and the low expression of LAIR-1 in decidual and decidual NK cells was also associated with spontaneous abortion. Correlation. Second part LAIRs and collagen molecules interact to regulate the phenotype of NK cells to analyze the interaction between LAIR-1 and collagen molecules, and the regulation of the expression of surface receptors and intracellular cytokines in peripheral NK cells and decidua NK cells. Methods routine aseptic isolation of peripheral blood mononuclear cells (PBMC) and decidua immunization After DIC, the magnetic beads were selected for the separation of peripheral NK cells and decidua NK cells, and the collagen molecules were added to the culture system in vitro. The expression of collagen molecular receptor LAIR-1 was analyzed with polymerase chain reaction (PCR) and flow cytometry (FCM), and collagen molecules were added to the early pregnancy NK cell culture system. The LAIR-2 treatment group was set up to analyze the expression of activator and inhibitory receptor on the surface of NK cells and the expression of Thl, Th2 type cytokine and cytotoxic activity related molecules on the surface of NK cells. Results collagen molecules can induce the expression of LAIR-1 in mRNA and protein levels in NK cells in a dose-dependent manner. The expression of NKp30 on the surface of the decidua NK cell can be reduced by interaction with LAIR-1, and the expression of the inhibitory receptor KIR2DL1 is up-regulated, and the interaction of collagen molecules and LAIR-1 can also reduce the expression of IFN- gamma TNF-a in the decidua NK cell Thl cell factor, without affecting Th2 cytokine IL-4 and NK cells in the decidua NK cells. The expression of IL-10, high concentration collagen molecules can reduce the expression of perforin in decidual NK cells, and the expression of the latter is inversely proportional to the fluorescence intensity of]LAIR-1 expression. This action, and the regulation of collagen molecules on the phenotype of NK cells and the expression of Thl type cytokines, can be antagonized by LAIR-2. Conclusion collagen molecules up regulation of NK cells. The expression of medium LAIR-1 and the interaction with LAIR-1 can reduce the expression of Th1 type cytokine and perforin in NK cells and induce the tolerance phenotype of decidual NK cells. Third trophoblast and decidual stromal cells are involved in regulating the function of decidua NK cells through collagen molecules to analyze the nourishment of mother fetal interface in early pregnancy. Cell and decidual matrix cells regulate the phenotype of decidual NK cells by expression of collagen molecules. Methods human early gestational trophoblastic cells were established in vitro, decidual stromal cells were cultured separately, and trophoblast and decidual stromal cells co culture system was used to simulate the microenvironment of mother fetal interface in early pregnancy, and then the purified decidua NK was fine. The LAIR-2 treatment group was established and the expression of the surface activator and inhibitory receptor and the cytokine and cytokine related molecules in the decidua NK cells were analyzed by flow cytometry (FCM). The P4H shRNA plasmid was further transfected to the trophoblast and decidua matrix cells to simulate the mother fetal interface collagen eggs of natural abortion. The low level expressed microenvironment of the white molecule was detected by polymerase chain reaction (PCR), enzyme linked immunosorbent assay (ELISA) and amino acid analyzer to detect the expression of collagen protein in the cultured and co cultured system of trophoblast and decidual stromal cells, but then FCM was used to analyze the activation receptors and inhibition of the surface of the decidua NK cells. The expression of the cytokine and cytokine and cytokine in the cell can be expressed in the trophoblast and decidual stromal cells to reduce the expression of the active receptor NKp30 of the decidual NK cell, up the expression of the inhibitory receptor KIR2DL1, and to reduce the Thl type of the decidual NK cells by the interaction of collagen molecules with LAIR-1 Cytokine IFN-y and]TNF-a, and the expression of perforin. The use of LAIR-2 blocking and P4H shRNA plasmid transfection by gene silencing collagen synthesis can inhibit the regulating effect of trophoblast and decidual matrix cells on the surface receptor, cytokine and cytotoxic activity of decidual NK cells. It is worth mentioning that the transfection of P4H shRNA plasmids is the key to the regulation of the cytokine and cytokine activity of decidual NK cells. The expression level of Th2 cytokine IL-4 and IL-10 in decidual NK cells decreased in the trophoblast and decidual matrix cells. Conclusion early pregnancy trophoblast and decidual stromal cells can regulate the function of the decidua NK cells through the expression of collagen molecules, which is beneficial to the maintenance of normal pregnancy. The fourth part of the JAK-STAT signaling pathway is useful. The regulation of LAIR-1 on NK cells aims to analyze the signaling pathway of LAIR-1 to regulate the function of NK cells. Methods the collagen molecules were added to the purified peripheral NK cells (pNK) and decidual NK cells (dNK) in vitro culture system, and the supernatant (Culture Medium, CM) cultured with shRNA transfected trophoblast and decidual matrix (Culture Medium) After the cell, the expression of STAT1, p-STAT1, STAT4, p-STAT4 in the LAIR-1 and AK-STAT signaling pathways was analyzed by immunoblotting (Western Blot), and the expression of the downstream related transcription factors and the expressions of the downstream related transcription factors were analyzed by Western Blot and flow cytometry (FCM). The relationship between JAK1, JAK2 and SHP-1, and the interaction between SHP-1 and LAIR-1, and the interaction between SHP-1 and LAIR-1. Construction of LAIR-1 over expressed stable cell line NK-92-LAIR-1 with virus plasmids and identification by QPCR, Western Blot and fluorescence microscopy to further differentiate the expression of STATs and LAIR-1 from the activation state. Under the stimulation of collagen molecules, LAIR-1 can raise SHP-1, and through the direct action of the latter and JAK1, JAK2, it inhibits the activation of STAT1 and STAT4 in the JAK-STAT signaling pathway, and then affects the expression of the transcription factor T-bet and Helios, and has successfully constructed the NK-92-LAIR-1. conclusion of the LAIR-1 overexpressed stable cell line. The JAK-STAT signaling pathway participates in the regulation of LAIR-1 and collagen molecular interaction on NK cells and the establishment of.LAIR-1 over expressed stable cell lines has laid a solid foundation for our further systematic research on the later system.
【學位授予單位】：復旦大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R714

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