Autoimmune Regulator gene (Aire)-mediated tolerance to pregnancy-associated self-antigens

自身免疫调节基因（Aire）介导的对妊娠相关自身抗原的耐受性

• 批准号: 10684826
• 负责人: Tippi Mackenzie
• 金额: $ 77.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684826
• 关键词: Ablation; Alloantigen; Allogenic; Antibodies; Antigens; Autoantigens; Autoimmune; Autoimmune Process; Autoimmunity; Biochemical; Biological; Bone Marrow; Cells; Chimera organism; Chronic; Clonal Deletion; Data; Decidua; Embryo; Embryo Resorption; Endometrium; Failure; Fetus; Functional disorder; Generations; Genes; Genetic Transcription; Genome; Goals; Health; Hormonal; Human; Immune; Immune Tolerance; Immune response; Immunologics; Immunologist; Infertility; Intervention; Late pregnancy; Life; Link; Literature; Maternal Exposure; Mediating; Modeling; Mothers; Mus; Organ; Patients; Phenotype; Placenta; Pregnancy; Pregnancy Complications; Pregnancy loss; Process; Reaction; Receptor Activation; Recurrence; Regulator Genes; Regulatory T-Lymphocyte; Reporter; Reporting; Role; Serum; Specimen; Spleen; Spontaneous abortion; Supporting Cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Time; Tissues; Transgenic Mice; Transgenic Organisms; Uterus; Work; antigen-specific T cells; autoreactive T cell; autoreactivity; candidate identification; cell type; clinically relevant; conditioning; draining lymph node; early pregnancy loss; experimental study; failure Implantation; fertility preservation; fetal; healthy pregnancy; insight; lymph nodes; maternal immune system; mouse model; novel; novel therapeutics; postnatal; pregnancy failure; pregnant; prevent; reproductive; response; targeted treatment; tool; transcriptomics

PROJECT SUMMARY The question of how the fetus and placenta avoid rejection by the maternal immune system has puzzled generations of immunologists and reproductive biologists. A great deal of work on this immunological paradox has focused on the problem of how the maternal immune system tolerates fetal alloantigens. However, another problem during pregnancy entails the exposure of the mother to numerous newly-induced or strongly upregulated self-antigens encoded by the mother’s own genome. Many of these “pregnancy associated antigens” (PAAs) have not been produced since the mother herself was a fetus with a placenta and are only encountered in postnatal life when she becomes pregnant. A crucial component in imposing tolerance to self- antigens is the autoimmune regulator gene (Aire), which promotes the expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs) and extrathymic cells Aire expressing cells (eTACs), leading to clonal deletion or Treg conversion of self-reactive T cells. The role of Aire in supporting healthy pregnancy has not yet been explored. Surprisingly, we found that selective depletion of maternal Aire-expressing cells in mice during early in pregnancy results in a dramatic phenotype of pregnancy loss (both failure to become pregnant after plugging and early embryo resorption), along with a significant increase in the conventional T cell to Treg cell ratio in the thymus and an influx of maternal T cells into the resorbing uterus. These data are consistent with other hints in the literature such as the presence of anti-placental antibodies and pregnancy complications (such as fetoplacental insufficiency) in patients with Aire deficiency. Based on these data, we hypothesize that Aire-mediated expression of PAAs in mTECs and eTACs supports healthy pregnancy by promoting deletion of PAA-reactive T cells and induction of PAA-specific Tregs. By extension, immune responses to these antigens in the absence of Aire may play a role in pregnancy complications. This hypothesis shifts the current paradigm regarding maternal-fetal tolerance from focusing on the potential threat of alloantigens to the unknown potential value of imposing tolerance to a unique set of PAAs encoded by the maternal genome. In this proposal, we will first assess the temporal role of Aire during early vs late pregnancy and the relative contributions of mTECs vs eTACs in supporting healthy pregnancy (Aim 1). We will use a combination of unbiased biochemical and transcriptomic analyses to identify putative Aire-regulated PAAs and validate their expression in mice and in patients with infertility (Aim 2). Lastly, we will investigate the function of Aire in generating PAA-specific Tregs using a novel transgenic mouse to express a model antigen under the control of Aire in maternal mTECs and eTACs (Aim 3). Our short-term goal is to understand the mechanisms by which Aire supports healthy pregnancy. Our long-term goal is to identify specific PAAs and immune derangements in patients with infertility. Responses to these questions could provide key insights that will lead to targeted therapies for this important health problem.

项目摘要 胎儿和胎盘如何避免被母体免疫系统排斥的问题一直困扰着 免疫学家和生殖生物学家的努力。关于这个免疫学悖论的大量研究 已经集中在母体免疫系统如何耐受胎儿同种异体抗原的问题上。但另一 怀孕期间的问题需要母亲暴露于许多新诱导的或强烈的 由母亲自身基因组编码的上调自身抗原。其中许多“妊娠相关” 由于母亲本身是一个有胎盘的胎儿，因此没有产生“抗原”（PAA）， 当她怀孕时，她会在产后生活中遇到。对自我宽容的一个重要组成部分- 抗原是自身免疫调节基因（Aire），其促进组织限制性抗原的表达 在胸腺髓质上皮细胞（mTEC）和胸腺外细胞Aire表达细胞（eTAC）中，导致 自身反应性T细胞的克隆缺失或Treg转化。Aire在支持健康妊娠方面的作用 尚未被探索。令人惊讶的是，我们发现选择性地去除小鼠母体中表达Aire的细胞， 在妊娠早期导致妊娠丢失的戏剧性表型（两个失败怀孕 堵塞和早期胚胎吸收后），沿着常规T细胞对Treg的显著增加 胸腺中的T细胞比例以及母体T细胞流入吸收子宫。这些数据是一致 文献中还有其他提示，如抗胎盘抗体和妊娠并发症的存在 (such胎儿胎盘功能不全）。根据这些数据，我们假设， Aire介导的mTEC和eTAC中PAA的表达通过促进缺失 PAA反应性T细胞和PAA特异性Treg的诱导。通过扩展，对这些抗原的免疫应答 在没有Aire的情况下，可能会在妊娠并发症中发挥作用。这一假设改变了当前的范式 关于母胎耐受，从关注同种异体抗原的潜在威胁到未知的潜在威胁， 对由母体基因组编码的一组独特的PAA施加耐受性的价值。在本提案中，我们将 首先评估Aire在妊娠早期与晚期的时间作用，以及mTECs与 eTAC支持健康妊娠（目标1）。我们将使用无偏见的生物化学和 转录组学分析以鉴定推定的Aire调节的PAA并验证它们在小鼠和小鼠中的表达。 不孕症患者（目标2）。最后，我们将研究Aire在产生PAA特异性TbR中的功能 使用新的转基因小鼠在母体mTEC中表达Aire控制下的模型抗原， eTAC（目标3）。我们的短期目标是了解Aire支持健康的机制， 怀孕我们的长期目标是确定不孕症患者的特定PAA和免疫紊乱。 对这些问题的回答可以提供关键的见解，这将导致针对这一重要疾病的靶向治疗。 健康问题。