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: 10219063
• 负责人: Tippi Mackenzie
• 金额: $ 78.89万
• 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/10219063
• 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; Immune system; Immunologics; Immunologist; Infertility; Intervention; Late pregnancy; Lead; Life; Link; Literature; Maternal Exposure; Mediating; Modeling; Mothers; Mus; Organ; Patients; Phenotype; Placenta; Play; 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; base; cell type; clinically relevant; conditioning; draining lymph node; early pregnancy loss; experimental study; failure Implantation; fertility preservation; fetal; healthy pregnancy; insight; lymph nodes; 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plapeta如何避免被产妇免疫系统拒绝的问题困惑 几代免疫学家和生殖生物学家。关于这种免疫悖论的大量工作 已经关注母体免疫系统如何耐受胎儿同抗原的问题。但是，另一个 怀孕期间的问题需要母亲暴露于众多新诱导或强烈的 由母亲自己的基因组编码的自我抗原上调。其中许多“与怀孕有关 抗原”（Paas）没有生产，因为母亲本人是一个有子宫的胎儿，只有 她怀孕时在产后生活中遇到。对自我施加宽容的关键组成部分 抗原是自身免疫调节剂基因（AIRE），它促进了组织限制抗原的表达 在髓质胸腺上皮细胞（MTEC）和外激体细胞AIRE表达细胞（ETAC）中，导致 自反应性T细胞的克隆缺失或Treg转换。 AIR在支持健康怀孕中的作用 尚未探索。令人惊讶的是，我们发现小鼠表达母体AIRE细胞的选择性耗竭 在怀孕的早期，导致怀孕丧失的戏剧性表型（均未怀孕 插入和早期胚胎分辨率），以及传统的T细胞到Treg的显着增加 胸腺中的细胞比率和母体T细胞进入吸收子宫的影响。这些数据是一致的 文献中的其他提示，例如存在抗位置抗体和妊娠并发症 （例如AIRE缺乏症患者）（例如胎儿阶段不足）。基于这些数据，我们假设 AIRE介导的PAA在MTEC和ETAC中的表达通过促进缺失来支持健康的怀孕 PAA反应性T细胞和PAA特异性Treg的诱导。通过扩展，对这些抗原的免疫回报 在没有AIR的情况下，可能在怀孕并发症中发挥作用。该假设改变了当前的范例 关注的母校宽容从专注于同种抗原的潜在威胁到未知的潜力 对由母体基因组编码的独特的PAA施加耐受性的价值。在此提案中，我们将 首先评估AIR在早期妊娠中的临时作用，以及MTECS与MTEC的相对贡献 ETAC支持健康妊娠（AIM 1）。我们将使用公正的生化和 转录组分析以识别推定的AIRE调节的PAA，并验证其在小鼠和 不育患者（AIM 2）。最后，我们将研究AIRE在生成PAA特异性Treg中的功能 使用新型的转基因小鼠在母体MTEC和AIR的控制下表达模型抗原， ETAC（AIM 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和免疫发育。 对这些问题的回答可能会提供关键的见解，从而为这一重要的疗法带来针对性的疗法 健康问题。