Maternal Central Immune Tolerance in Reproduction

母体生殖中枢免疫耐受

• 批准号: 10617856
• 负责人: MARGARET G PETROFF
• 金额: $ 39.96万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-13 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617856
• 关键词: Adult; Allografting; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Cells; Data; Diagnosis; Disease; Embryo; Embryo Loss; Embryo Transfer; Ensure; Estrogens; Fertility; Fetal Growth Retardation; Fetus; Foundations; Gene Expression; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Gonadal structure; Gravid; Hormones; Immune; Immune Tolerance; Immune system; Immunologic Surveillance; Immunosuppression; In Vitro; Infertility; Inherited; Knockout Mice; Knowledge; Link; Malignant Neoplasms; Maps; Maternal-Fetal Exchange; Mediating; Mus; Oocytes; Ovarian; Ovary; Peripheral; Personal Satisfaction; Physiological; Placenta; Play; Population; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy loss; Premature Birth; Prevention strategy; Process; Progesterone; Progesterone Receptors; Proteins; Regulation; Regulatory T-Lymphocyte; Reporting; Reproduction; Reproductive Health; Reproductive system; Research; Role; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Time; Tissues; Transplantation Immunology; Uterus; Woman; Work; age related; base; blastocyst; central tolerance; combat; embryo quality; embryo/fetus antigen; embryonic stem cell; experimental study; failure Implantation; female fertility; fetal; fetal loss; healthy pregnancy; immune function; implantation; in vivo; in vivo Model; insight; intimate behavior; maternal immune system; mouse model; natural Blastocyst Implantation; novel; pregnancy disorder; progesterone receptor A; reproductive; reproductive function; reproductive outcome; reproductive tract; societal costs; transcription factor; tumor immunology

The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which antigenically unique, tissue-specific proteins are introduced to the mother’s immune system at the commencement and for the duration of pregnancy. When this tolerance fails, infertility, preterm birth and delivery, preeclampsia, or fetal growth restriction may result. Aire is a transcriptional regulator that induces expression of tissue-restricted genes in the thymus, wherein central tolerance to many self-antigens is acquired. Aire ensures that tolerance to such antigens is established in developing T cells. Tissue-restricted genes regulated by Aire include many that are specific to the fetus and placenta, and we have found not only that Aire is upregulated in the thymus during pregnancy, but also that global Aire deficiency can predispose dams to fetal loss. Intriguingly, our group and others have also identified Aire expression in the ovary and uterus, suggesting an additional, extrathymic role of this transcription factor. In this project, we aim to define the role of Aire in immune tolerance to the fetus, elucidate its regulation by sex hormones, and clarify its immune- independent role in reproduction. We will test the overall hypothesis that Aire is required for central immune tolerance the fetus, and that it functions in parallel within the uterus and ovary to support fertility. We propose two specific aims: Aim 1. Determine the impact of Aire deficiency on maternal immune tolerance to the fetus. Aim 2. Ascertain the functional connection between sex hormones and Aire in maternal central tolerance to the fetus. Aim 3. Identify the immune-independent function of Aire in female fertility. The results of these experiments are expected to provide highly novel insight into as-yet unexplored mechanisms of maternal tolerance to the fetal-placental unit, female fertility, and the regulation thereof by sex hormones, greatly advancing our understanding of maternal tolerance to the fetal allograft. The results will have far-reaching implications for women’s wellbeing in the fields of pregnancy, reproductive health, autoimmune disease, transplantation, and cancer immunology.

这项研究的总体目的是了解怀孕对胎儿的孕产妇免疫耐受性的机制。母体免疫系统与胎儿同种异体移植之间的亲密关系是一种无与伦比的身体状况，在这种情况下，抗原独特的，组织特异性的蛋白质在开始时和怀孕期间被引入母亲的免疫系统。当这种公差失败时，可能会导致不育，早产和分娩，先兆子痫或胎儿生长限制。 AIRE是一种转录调节剂，它影响胸腺中组织限制基因的表达，其中获得了许多对许多自抗原的中心耐受性。 AIRE确保在发育中的T细胞中确定对这种抗原的耐受性。由AIRE调节的组织限制基因包括许多特定于胎儿和plap片的基因，我们不仅发现AIRE在怀孕期间在胸腺中进行了更新，而且全球AIRE缺乏症可以使胎儿损失易感性。有趣的是，我们的群体和其他人也鉴定出卵巢和子宫中的AIR表达，这表明该转录因子的额外的外激发作用。在这个项目中，我们旨在定义AIR在免疫容忍胎儿中的作用，通过性恐怖阐明其调节，并阐明其在生殖中的免疫独立作用。我们将检验总体假设，即胎儿中央免疫耐受性需要AIRE，并且它在子宫内和卵巢中并行起作用以支持生育能力。我们提出了两个具体的目标：目标1。确定AIRE缺乏对胎儿的遗传免疫耐受性的影响。目标2。确定性恐怖与AIRE之间的功能连接，以对胎儿的中心宽容。目标3。确定AIR在女性生育中的免疫独立功能。这些实验的结果有望提供高度新颖的洞察力，以了解对胎儿单位，女性生育能力以及性马的调节的孕妇耐受性的意外机制，从而很好地促进了我们对胎儿对胎儿同种异体移植的耐受的理解。结果将对怀孕，生殖健康，自身免疫性疾病，移植和癌症免疫学领域的妇女健康具有深远的影响。

项目成果

Fetal-placental antigens and the maternal immune system: Reproductive immunology comes of age.

• DOI: 10.1111/imr.13090
• 发表时间: 2022-07
• 期刊: Immunological reviews
• 影响因子: 8.7

Nuclear Progesterone Receptor Expressed by the Cortical Thymic Epithelial Cells Dictates Thymus Involution in Murine Pregnancy.

• DOI: 10.3389/fendo.2022.846226
• 发表时间: 2022
• 期刊: FRONTIERS IN ENDOCRINOLOGY
• 影响因子: 5.2
• 作者: Ahn, Soo Hyun;Nguyen, Sean L.;Kim, Tae Hoon;Jeong, Jae-Wook;Arora, Ripla;Lydon, John P.;Petroff, Margaret G.
• 通讯作者: Petroff, Margaret G.

Production and Composition of Group B Streptococcal Membrane Vesicles Vary Across Diverse Lineages.

• DOI: 10.3389/fmicb.2021.770499
• 发表时间: 2021
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: McCutcheon CR;Pell ME;Gaddy JA;Aronoff DM;Petroff MG;Manning SD
• 通讯作者: Manning SD