子宮NK細胞在ASD中作用機制
發(fā)布時間：2018-07-28 08:40
【摘要】：人體的免疫系統(tǒng)是一個相互制衡的穩(wěn)態(tài)環(huán)境。作為孕育新生命的子宮,承擔著作為一個物種繁衍后代的歷史使命。近些年來,子宮免疫環(huán)境的研究越來越受重視。而子宮對于胚胎的耐受機制也一直是人們的研究熱點。在子宮當中,除了子宮內(nèi)膜細胞,胎兒的滋養(yǎng)層細胞外,還有一群在母胎界面無處不在的免疫細胞,包括巨噬細胞、DC細胞、T淋巴細胞、NK細胞等。這其中作為自然殺傷細胞的NK細胞自然不容忽視。在以往的研究中,發(fā)現(xiàn)NK細胞除了行使其殺傷功能外。處于子宮當中的NK細胞,還行使著維持母胎界面免疫耐受的功能。ASD又被稱為自閉癥譜系障礙,是一種嚴重普遍的神經(jīng)發(fā)育障礙。根據(jù)美國最新的精神病協(xié)會(DSM-V),將ASD臨床表現(xiàn)描述為按社交障礙和重復刻板行為。而我們?nèi)粘Ｋ盍私獾淖蚤]癥(autistic disorder)則是其中最嚴重的一種疾病形式。ASD患者多為兒童時期即發(fā)病,并且在日后的生活中并不能得到非常有效的治療,使這一類人在社會互動,言語或非言語交際上受到嚴重的限制。并且長此以往,也給家庭帶來了沉重的負擔。正因為如此,全世界對于ASD的研究層出不窮。在本研究中,我們試圖從母胎界面的子宮NK細胞入手,來揭開ASD疾病的一層薄紗。首先,我們通過向C57BL/6J小鼠腹腔注射TLR3激動劑poly(I:C),觀察到小鼠容易出現(xiàn)流產(chǎn)的狀況,并且胎鼠的生長發(fā)育嚴重受限。胎鼠的大腦皮層結構混亂無序,出現(xiàn)ASD疾病中大腦皮層會出現(xiàn)的現(xiàn)象。接著,我們對小鼠的子宮免疫細胞進行了檢測。發(fā)現(xiàn)經(jīng)過poly (I:C)處理的小鼠子宮當中,子宮NK細胞的比例發(fā)生明顯降低。CD49a+Eomes+的子宮NK細胞被認為是子宮所獨有的組織居留細胞。E12.5天,用poly(I:C)處理孕鼠之后,CD49a+Eomes+的子宮NK細胞的比例也發(fā)生明顯下降。E13.5天,我們檢測到子宮中的CD4+T細胞分泌IL-17A的水平明顯提高,即子宮Th17細胞比例增多。而子宮NK細胞,其分泌IFN-γ的能力下降,分泌顆粒酶B的能力增強。研究表明子宮NK細胞可以通過IFN--γ來負調(diào)子宮Th17細胞分泌IL-17A的能力。并且ASD發(fā)病的重要原因就是母胎界面IL-17A大量增多,通過母胎血腦屏障與胎兒大腦內(nèi)的IL-17A受體相結合,最終導致大腦皮層結構的錯亂。因此我們猜測子宮NK細胞可能可以通過分泌IFN-γ來阻止ASD的發(fā)生。我們選擇了 IFN-γ分泌缺陷的T-bet缺陷鼠和缺乏NK細胞的Nfil3缺陷鼠,進行進一步的檢測。發(fā)現(xiàn)相比較WT鼠而言,T-bet缺陷鼠更容易發(fā)生IL-17A的高水平分泌。而Nfil3缺陷鼠則在子宮居留NK細胞比例上低于WT鼠,并且大腦發(fā)育結構錯亂。由此,驗證了子宮NK細胞對于大腦發(fā)育和維持母胎免疫環(huán)境穩(wěn)定的重要性。子宮NK細胞可以通過IFN-γ的水平來加重或者延緩ASD發(fā)生的可能。進一步,我們選擇了人體正常妊娠的子宮細胞,并且將子宮淋巴細胞與滋養(yǎng)層細胞在體外共同培養(yǎng),并且用poly (I:C)刺激。人體子宮NK細胞的比例并沒有發(fā)生改變,但是其分泌IFN-γ的能力發(fā)生了下降。綜上所述,本實驗驗證了子宮NK細胞在維持母胎界面IL-17A水平從而防止ASD發(fā)生的重要作用。子宮NK細胞能夠通過分泌IFN-γ來制衡Th17細胞分泌IL-17A水平。這在將來可能成為一種根治ASD疾病的治療方式。
[Abstract]:The immune system of the human body is a steady state of balance. As the womb of breeding new life, it bears the historical mission of developing the offspring as a species. In recent years, the research on the immune environment of the uterus has been paid more and more attention. And the mechanism of the womb's tolerance to the embryo has always been a hot spot of research. In the womb, except the child. Endometrium cells, outside the fetal trophoblast cells, and a group of immune cells that are ubiquitous in the maternal fetal interface, including macrophages, DC cells, T lymphocytes, NK cells, etc., in which the NK cells, as natural killer cells, can not be ignored. In the previous study, the NK cells were found in the womb in addition to their killing function. NK cells, also known as autism spectrum disorders, are also known as autism spectrum disorders, which are also known as autism spectrum disorders, which maintain the maternal fetal interface immune tolerance. According to the latest American Psychiatric Association (DSM-V), the ASD clinical manifestations are described as social disorders and repeated plates, and our daily best knowledge of autism (auti Stic disorder) is the most serious form of disease in which.ASD patients are mostly in childhood, and they are not very effective in their future life, making this kind of people severely restricted in social interaction, speech or nonverbal communication. And, in the long run, the family has also brought heavy burden to the family. For this reason, the world's research on ASD is endless. In this study, we tried to start a layer of ASD disease from the NK cells of the womb at the mother's interface. First, by injecting the TLR3 agonist poly (I:C) into the abdominal cavity of the C57BL/6J mice, we observed that the mice were prone to miscarriage, and the growth of fetal mice was Fa Yuyan. The cerebral cortex disorder and disorder of the fetal rat's cerebral cortex appeared in the cerebral cortex in ASD disease. Then, we detected the uterine immune cells in mice. It was found that in the uterus of the mice treated with poly (I:C), the proportion of NK cells in the uterus was significantly reduced by.CD49a+Eomes+ in the uterus, and the NK cells in the uterus were considered to be the uterus. After.E12.5 days, the proportion of NK cells in the uterus of CD49a+Eomes+ was significantly decreased after poly (I:C) treatment. We detected that the level of IL-17A in the CD4+T cells in the uterus increased significantly, that is, the proportion of Th17 cells in the uterus increased. And the NK cells of the uterus decreased and secreted the IFN- gamma. The ability of the granzyme B is enhanced. The study shows that the uterine NK cells can negatively regulate the secretion of IL-17A in the Th17 cells of the uterus through IFN-- gamma. And the important reason for the pathogenesis of ASD is that the maternal fetal interface IL-17A increases greatly, and the maternal fetal blood brain barrier is combined with the IL-17A receptor in the fetal brain to eventually lead to the disorder of the cortical structure. We hypothesized that uterine NK cells may be able to prevent the occurrence of ASD by secreting IFN- gamma. We chose T-bet deficient rats with IFN- gamma deficiency and Nfil3 deficient mice lacking NK cells for further detection. It was found that T-bet deficient rats were more likely to produce high levels of IL-17A in WT mice, while Nfil3 deficient mice were in the uterus. The proportion of NK cells in residence is lower than that of WT mice, and the developmental structure of the brain is disorderly. Thus, the importance of the NK cells in the uterus to the development of the brain and to maintain the stability of the maternal fetal immune environment. The uterus NK cells can increase or postpone the occurrence of ASD through the level of IFN- gamma. Further, we choose the uterus cells of normal pregnancy. The percentage of NK cells in the human uterus has not changed, but the ability to secrete IFN- gamma in human uterus has declined. In summary, this experiment verified the importance of the NK cells in the womb to maintain the IL-17A level of the maternal fetal interface to prevent the occurrence of ASD in vitro. NK cells can secrete IFN- gamma to balance the level of IL-17A secreted by Th17 cells, which may become a way to cure ASD diseases in the future.
【學位授予單位】：中國科學技術大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R749.94
本文編號：2149537
[Abstract]:The immune system of the human body is a steady state of balance. As the womb of breeding new life, it bears the historical mission of developing the offspring as a species. In recent years, the research on the immune environment of the uterus has been paid more and more attention. And the mechanism of the womb's tolerance to the embryo has always been a hot spot of research. In the womb, except the child. Endometrium cells, outside the fetal trophoblast cells, and a group of immune cells that are ubiquitous in the maternal fetal interface, including macrophages, DC cells, T lymphocytes, NK cells, etc., in which the NK cells, as natural killer cells, can not be ignored. In the previous study, the NK cells were found in the womb in addition to their killing function. NK cells, also known as autism spectrum disorders, are also known as autism spectrum disorders, which are also known as autism spectrum disorders, which maintain the maternal fetal interface immune tolerance. According to the latest American Psychiatric Association (DSM-V), the ASD clinical manifestations are described as social disorders and repeated plates, and our daily best knowledge of autism (auti Stic disorder) is the most serious form of disease in which.ASD patients are mostly in childhood, and they are not very effective in their future life, making this kind of people severely restricted in social interaction, speech or nonverbal communication. And, in the long run, the family has also brought heavy burden to the family. For this reason, the world's research on ASD is endless. In this study, we tried to start a layer of ASD disease from the NK cells of the womb at the mother's interface. First, by injecting the TLR3 agonist poly (I:C) into the abdominal cavity of the C57BL/6J mice, we observed that the mice were prone to miscarriage, and the growth of fetal mice was Fa Yuyan. The cerebral cortex disorder and disorder of the fetal rat's cerebral cortex appeared in the cerebral cortex in ASD disease. Then, we detected the uterine immune cells in mice. It was found that in the uterus of the mice treated with poly (I:C), the proportion of NK cells in the uterus was significantly reduced by.CD49a+Eomes+ in the uterus, and the NK cells in the uterus were considered to be the uterus. After.E12.5 days, the proportion of NK cells in the uterus of CD49a+Eomes+ was significantly decreased after poly (I:C) treatment. We detected that the level of IL-17A in the CD4+T cells in the uterus increased significantly, that is, the proportion of Th17 cells in the uterus increased. And the NK cells of the uterus decreased and secreted the IFN- gamma. The ability of the granzyme B is enhanced. The study shows that the uterine NK cells can negatively regulate the secretion of IL-17A in the Th17 cells of the uterus through IFN-- gamma. And the important reason for the pathogenesis of ASD is that the maternal fetal interface IL-17A increases greatly, and the maternal fetal blood brain barrier is combined with the IL-17A receptor in the fetal brain to eventually lead to the disorder of the cortical structure. We hypothesized that uterine NK cells may be able to prevent the occurrence of ASD by secreting IFN- gamma. We chose T-bet deficient rats with IFN- gamma deficiency and Nfil3 deficient mice lacking NK cells for further detection. It was found that T-bet deficient rats were more likely to produce high levels of IL-17A in WT mice, while Nfil3 deficient mice were in the uterus. The proportion of NK cells in residence is lower than that of WT mice, and the developmental structure of the brain is disorderly. Thus, the importance of the NK cells in the uterus to the development of the brain and to maintain the stability of the maternal fetal immune environment. The uterus NK cells can increase or postpone the occurrence of ASD through the level of IFN- gamma. Further, we choose the uterus cells of normal pregnancy. The percentage of NK cells in the human uterus has not changed, but the ability to secrete IFN- gamma in human uterus has declined. In summary, this experiment verified the importance of the NK cells in the womb to maintain the IL-17A level of the maternal fetal interface to prevent the occurrence of ASD in vitro. NK cells can secrete IFN- gamma to balance the level of IL-17A secreted by Th17 cells, which may become a way to cure ASD diseases in the future.
【學位授予單位】：中國科學技術大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R749.94
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