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

基本信息

批准号：
10455466
负责人：
Tippi Mackenzie
金额：
$ 78.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10455466
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

项目摘要

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.

项目概要胎儿和胎盘如何避免母体免疫系统排斥的问题一直令人困惑几代免疫学家和生殖生物学家对这一免疫悖论进行了大量的工作。然而，另一个问题是母体免疫系统如何耐受胎儿同种抗原。怀孕期间的问题导致母亲接触大量新诱发的或强烈的由母亲自身基因组编码的自身抗原上调，其中许多“与怀孕相关”。由于母亲本身还是有胎盘的胎儿，因此尚未产生“抗原”（PAA），并且仅这是她怀孕时在产后生活中遇到的一个重要组成部分。抗原是自身免疫调节基因（Aire），它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。令人惊讶的是，我们发现小鼠中母体 Aire 表达细胞的选择性缺失。怀孕早期会导致戏剧性的流产表型（均未能怀孕）堵塞和早期胚胎吸收后），同时常规 T 细胞显着增加至 Treg 胸腺中的细胞比例和母体 T 细胞流入再吸收子宫的情况这些数据是一致的。文献中的其他提示，例如抗胎盘抗体的存在和妊娠并发症（例如胎儿胎盘功能不全）艾尔缺乏症患者基于这些数据，我们勇敢地承认。 mTEC 和 eTAC 中 Aire 介导的 PAAs 表达通过促进删除来支持健康妊娠 PAA 反应性 T 细胞和 PAA 特异性 Tregs 的诱导进而，对这些抗原产生免疫反应。在缺乏艾尔的情况下，这一假设可能会在妊娠并发症中发挥作用。关于母胎耐受性从关注同种异体抗原的潜在威胁转向未知的潜力对母体基因组编码的一组独特的 PAAs 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 与妊娠晚期的相对贡献 eTAC 支持健康怀孕（目标 1）。我们将结合使用公正的生化和治疗方法。转录组分析以鉴定假定的 Aire 调节的 PAAs 并验证其在小鼠和体内的表达最后，我们将研究 Aire 在生成 PAA 特异性 Tregs 中的功能。使用新型转基因小鼠在母体 mTEC 中表达受 Aire 控制的模型抗原 eTAC（目标 3）。我们的短期目标是了解 Aire 支持健康的机制。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，从而为这一重要的疾病提供靶向治疗。健康问题。