STUDIES OF MATERNAL AND NEONATAL IMMUNITY

描述（由申请人提供）：滋养细胞表达MHC抗原的失败被认为是怀孕期间胎儿存活的必要条件。因此，保护生殖的强大进化压力可能会对这些基因产生严格的重叠调节控制。我们已经证明，在滋养细胞中，II类表达由至少两种控制机制介导，包括II类反激活子转录的抑制和上游负调控元件[NRE]。据报道，表达II类的B细胞与滋养层细胞融合导致异核体中CIITA基因沉默，表明滋养层细胞中存在抑制因子。滋养细胞II类的抑制被认为是由几种CIITA转录的候选抑制剂[Blimp-1， tgf - β]引起的。我们已经证明，低浓度的去乙酰化酶抑制剂[DAIs]可以激活滋养细胞上的II类和共刺激分子，而没有明显的CIITA。高浓度DAIs可诱导细胞周期阻滞和表达II类、cd40、cd80和CD86的细胞凋亡。该基金将探索由表观遗传因子（如乙酰化和甲基化）介导的滋养细胞II类激活的CIITA独立途径的可能性，并试图进一步定义潜在的分子途径。这些发现与胎儿滋养细胞启动免疫应答能力的生理学相关性将被研究。MHC和其他关键免疫基因的表达将在DAIs和类似的其他毒性物质产生的凋亡滋养细胞、外泌体衍生的滋养细胞系和新鲜小鼠滋养细胞上进行评估。希望这些研究能够增强我们对滋养细胞II类表达和某些其他免疫基因调控的一般机制的理解。这项工作也可以应用于临床相关领域，如流产、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.