子宫NK细胞在ASD中作用机制
发布时间：2018-07-28 08:40
【摘要】：人体的免疫系统是一个相互制衡的稳态环境。作为孕育新生命的子宫,承担着作为一个物种繁衍后代的历史使命。近些年来,子宫免疫环境的研究越来越受重视。而子宫对于胚胎的耐受机制也一直是人们的研究热点。在子宫当中,除了子宫内膜细胞,胎儿的滋养层细胞外,还有一群在母胎界面无处不在的免疫细胞,包括巨噬细胞、DC细胞、T淋巴细胞、NK细胞等。这其中作为自然杀伤细胞的NK细胞自然不容忽视。在以往的研究中,发现NK细胞除了行使其杀伤功能外。处于子宫当中的NK细胞,还行使着维持母胎界面免疫耐受的功能。ASD又被称为自闭症谱系障碍,是一种严重普遍的神经发育障碍。根据美国最新的精神病协会(DSM-V),将ASD临床表现描述为按社交障碍和重复刻板行为。而我们日常所最了解的自闭症(autistic disorder)则是其中最严重的一种疾病形式。ASD患者多为儿童时期即发病,并且在日后的生活中并不能得到非常有效的治疗,使这一类人在社会互动,言语或非言语交际上受到严重的限制。并且长此以往,也给家庭带来了沉重的负担。正因为如此,全世界对于ASD的研究层出不穷。在本研究中,我们试图从母胎界面的子宫NK细胞入手,来揭开ASD疾病的一层薄纱。首先,我们通过向C57BL/6J小鼠腹腔注射TLR3激动剂poly(I:C),观察到小鼠容易出现流产的状况,并且胎鼠的生长发育严重受限。胎鼠的大脑皮层结构混乱无序,出现ASD疾病中大脑皮层会出现的现象。接着,我们对小鼠的子宫免疫细胞进行了检测。发现经过poly (I:C)处理的小鼠子宫当中,子宫NK细胞的比例发生明显降低。CD49a+Eomes+的子宫NK细胞被认为是子宫所独有的组织居留细胞。E12.5天,用poly(I:C)处理孕鼠之后,CD49a+Eomes+的子宫NK细胞的比例也发生明显下降。E13.5天,我们检测到子宫中的CD4+T细胞分泌IL-17A的水平明显提高,即子宫Th17细胞比例增多。而子宫NK细胞,其分泌IFN-γ的能力下降,分泌颗粒酶B的能力增强。研究表明子宫NK细胞可以通过IFN--γ来负调子宫Th17细胞分泌IL-17A的能力。并且ASD发病的重要原因就是母胎界面IL-17A大量增多,通过母胎血脑屏障与胎儿大脑内的IL-17A受体相结合,最终导致大脑皮层结构的错乱。因此我们猜测子宫NK细胞可能可以通过分泌IFN-γ来阻止ASD的发生。我们选择了 IFN-γ分泌缺陷的T-bet缺陷鼠和缺乏NK细胞的Nfil3缺陷鼠,进行进一步的检测。发现相比较WT鼠而言,T-bet缺陷鼠更容易发生IL-17A的高水平分泌。而Nfil3缺陷鼠则在子宫居留NK细胞比例上低于WT鼠,并且大脑发育结构错乱。由此,验证了子宫NK细胞对于大脑发育和维持母胎免疫环境稳定的重要性。子宫NK细胞可以通过IFN-γ的水平来加重或者延缓ASD发生的可能。进一步,我们选择了人体正常妊娠的子宫细胞,并且将子宫淋巴细胞与滋养层细胞在体外共同培养,并且用poly (I:C)刺激。人体子宫NK细胞的比例并没有发生改变,但是其分泌IFN-γ的能力发生了下降。综上所述,本实验验证了子宫NK细胞在维持母胎界面IL-17A水平从而防止ASD发生的重要作用。子宫NK细胞能够通过分泌IFN-γ来制衡Th17细胞分泌IL-17A水平。这在将来可能成为一种根治ASD疾病的治疗方式。
[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.
【学位授予单位】：中国科学技术大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.94
本文编号：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.
【学位授予单位】：中国科学技术大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.94
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