STUDIES OF MATERNAL AND NEONATAL IMMUNITY

描述(由申请人提供)：滋养层细胞不表达MHC抗原被认为是妊娠期间胎儿存活的关键。因此，保护生殖的强大进化压力很可能会发展出对这些基因的紧密重叠的调控。我们已经证明，在滋养层细胞中，第二类基因的表达至少受到两种调控机制的调节，其中包括抑制第二类反式激活因子转录和上游负性调控元件[NRE]。有报道称，表达第II类基因的B细胞与滋养层细胞融合后，异核体中的CIITA基因沉默，提示滋养层细胞中存在一种抑制因子。滋养层细胞中II类基因的抑制被认为是由几种候选的CIITA转录抑制物[Blimp-1，TGF-β]所致。我们已经证明，低浓度的脱乙酰酶抑制剂[DAIS]激活滋养层细胞上的II类和共刺激分子，而没有明显的CIITA。高浓度的DAIS可诱导细胞周期阻滞，诱导表达II类、CD4O、CD8O和CD86类分子的细胞发生凋亡。这笔赠款将探索在滋养层细胞中由表观遗传剂(如乙酰化和甲基化)介导的II类激活的非CIITA途径的可能性，并试图进一步确定潜在的分子途径。这些发现与胎儿滋养层细胞启动免疫反应的能力的生理学相关性将被调查。MHC和其他关键免疫基因的表达将在DAIS和类似的其他毒物产生的凋亡滋养层细胞、外体来源的滋养层细胞系和新鲜的小鼠滋养层细胞上进行评估。希望这些研究能加深我们对滋养层细胞上调节第二类基因表达和某些其他免疫基因的一般机制的理解。这项工作也可能应用于具有临床意义的领域，如堕胎、自身免疫和癌症。

DESCRIPTION (provided by applicant): The failure of the trophoblast to express MHC antigens is believed to be essential for survival of the fetus during pregnancy. It is therefore likely that strong evolutionary pressures to preserve reproduction would develop tight overlapping regulatory controls of these genes. We have shown that in trophoblasts, class II expression is mediated by at least two control mechanisms involving repression of class II transactivator transcription and an upstream negative regulatory element [NRE]. Fusion of B cells expressing class II with trophoblast cells has been reported to result in silencing of the CIITA gene in the heterokaryon suggesting a repressor in the trophoblast. Repression of class II in trophoblast cells has been postulated to result from several candidate inhibitors of CIITA transcription [Blimp-1, TGF-beta]. We have demonstrated that low concentrations of deacetylase inhibitors [DAIs] activate class II and costimulatory molecules on trophoblast cells without demonstrable CIITA. DAIs at higher concentrations induce cell cycle blocks and apoptotic cells expressing class II, CD4O, CD8O and CD86. This grant will explore the possibility of a CIITA independent pathway of class II activation mediated by epigenetic agents, such as acetylation and methylation, in trophoblast cells and attempt to further define the underlying molecular pathways. The physiological relevance of these findings to the ability of the fetal trophoblast cells to initiate an immune response will be investigated. The expression of MHC and other key immune genes will be evaluated on apoptotic trophoblast cells produced by DAIs and similar other toxic agents and on exosome derived trophoblast cell lines and on fresh murine trophoblast cells. Hopefully, these studies will enhance our understanding of the general mechanisms that regulate class II expression and certain other immune genes on trophoblast cells. This work may also have application to areas of clinical relevance, such as abortion, autoimmunity and cancer.