母—胎免疫耐受研究进展

Research progress of maternal-fetal tolerance

正常妊娠是一个复杂的生理过程.胎儿虽携有遗传自父系的HLA抗原,但却并未引发母体产生针对胎儿这种特殊半同种"天然移植物"的排斥.妊娠期母-胎间必然存在着复杂的分子对话机制,以维持胎儿胎盘正常发育.母-胎交互对话异常,将引起母体对胚胎的免疫排斥(母-胎免疫调节紊乱),导致妊娠失败或妊娠并发症如自然流产、子痫前期等.母—胎对话的关键是母-胎免疫适应,而母—胎免疫适应的本质在于母体免疫系统对胚胎抗原的免疫耐受,其核心部位在母—胎界面;妊娠早期蜕膜局部出现免疫细胞亚群的富集和重分布,母体免疫系统不仅不排斥携有父系抗原的胚胎,反而形成母—胎免疫耐受,至今免疫生物学仍无法解释母—胎免疫相容的生理性机制.本文在总结既往研究成果的基础上,围绕母-胎界面关键的功能细胞,阐明基于母-胎交互对话的母-胎免疫耐受的建立和维持机制.

Development of the allogeneic fetus in the maternal uterus represents an immunological paradox. Successful pregnancy requires the maternal immune system to tolerate the semi-allogeneic fetus. A failure in immune tolerance may result in abnormal pregnancies, such as recurrent spontaneous abortion. These call for a better understanding of the mechanisms leading to maternal-fetal tolerance. As the only exception to the traditional immunological principles, maternal-fetal tolerance has always been the focus of attention in the fields of reproductive immunology. Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. The formation of a functional synapse of the invading fetal trophoblsats, maternal immune cells and decidual stromal cells have now been identified. An improved mechanistic understanding of maternal-fetal tolerance is emerging during the last century. During early pregnancy, the developing decidua undergoes dramatic changes in response to invading trophoblasts. Extravillous trophoblast（EVT） cells do not express major histocompatibility complex（MHC） class I human leukocyte antigens（HLA）-A and HLA-B, which are the main causes of CD8＋ T cell-mediated rejection. However, HLA-C and HLA-G, highly expressed on EVT cells, can elicit a direct tolerant response by NK cells in most cases. Furthermore, maternal immune cells could be educated by embryonic trophoblasts to develop a unique phenotype and tolerate the fetus. Decidual stromal cells（DSCs） are the predominant cell type of the maternal decidua and play a key role in embryo implantation and placentation. Apart from nutritive and endocrine functions, DSCs are believed to be involved in many immune activities, such as cytokine production and antigen presentation, and regulate the decidual immune responses that may lead to either a successful pregnancy or miscarriage. Howerer, there are still unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall and decidual stromal cells which are the largest number of cells in the decidua. Here we review the previous research results in the field, with a special focus on the establishment and maintenance mechanism of maternal-fetal tolerance based on the maternal-fetal crosstalk. Nevertheless, recent advances in molecular biology have dramatically enhanced our knowledge of the immunobiology of the maternal-fetal interface. Insights into maternal-fetal tolerance will not only advance our understanding of normal pregnancy but also may be helpful on how immune tolerance can be applied in therapeutic strategies to prevent pregnancy loss. Further research in these areas will give us more avenues for preventing pregnancy complication related to faulty maternal-fetal immune interactions.