Lymphocyte function in inflammatory disorders of human endometrium and decidua

淋巴细胞在人子宫内膜和蜕膜炎症性疾病中的功能

• 批准号: 10673395
• 负责人: Heather Huddleston
• 金额: $ 62.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673395
• 关键词: Address; Allografting; Antigens; Archives; Autoantigens; Autoimmune; B cell therapy; B-Lymphocytes; Beds; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cell Line; Cell Lineage; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chronic; Data; Decidua; Decidual Cell; Development; Developmental Process; Diagnostic; Disease; Endometrial; Endometrium; Ensure; Environment; Epigenetic Process; Epithelial Cells; Event; Female; Fertility; Fetal Development; Fibroblasts; First Pregnancy Trimester; Fostering; Frequencies; Genes; Goals; Human; Immune; Immunologics; Impairment; Infection; Infertility; Inflammation; Inflammatory; Invaded; Knowledge; Lymphocyte; Lymphocyte Function; Lymphocyte Subset; Maternal-Fetal Exchange; Mediating; Mediator; Menstrual cycle; Modeling; Natural Killer Cells; Obesity; Pathogenesis; Pathway interactions; Patients; Peptides; Phase; Phenotype; Placentation; Polycystic Ovary Syndrome; Population; Pregnancy; Pregnancy Outcome; Process; Proteome; Regulatory T-Lymphocyte; Reproduction; Role; Specificity; Specimen; Spiral Artery of the Endometrium; Stains; Subgroup; System; T-Cell Immunologic Specificity; T-Lymphocyte; Therapeutic; Thinness; Tissues; Uterus; Vascular remodeling; Villous; Woman; Work; comorbidity; early pregnancy; early pregnancy loss; endometriosis; experimental study; failure Implantation; fetal; immunoregulation; implantation; improved; insight; microbial; natural Blastocyst Implantation; novel; obese patients; prospective; reproductive; reproductive outcome; reproductive success; single cell technology; subfertility; success; transcriptome; trophoblast

Endometriosis and polycystic ovary syndrome (PCOS) are major causes of female subfertility and infertility. Each is accompanied by chronic endometrial inflammation triggered and perpetuated by uncertain mechanisms. Potential roles for immune cells, specifically T and B lymphocytes, in endometrial inflammation are largely unexplored despite their being key orchestrators and mediators of tissue inflammation in many other non-uterine contexts. Furthermore, the antigen specificities of endometrial T and B cells are not well described, and whether self-antigen specific clones contribute to disorders with poor reproductive outcomes is unclear, despite evidence that endometriosis, in particular, may have an autoimmune component. These knowledge gaps represent major opportunities for improving reproductive outcomes for infertile patients with endometriosis and PCOS. Moreover, these disorders represent ideal models for investigating how immune dysregulation in the endometrium may contribute to infertility and subfertility more broadly. Accordingly, the goal of this project is to determine how T and B cells contribute to the pathogenesis of endometrial inflammation and, by extension, decidual inflammation, relevant to implantation failure and poor pregnancy outcomes. Herein, we propose to deeply characterize the frequencies, transcriptomes, proteomes, TCR/BCR repertoires, and antigen specificities of endometrial and decidual T and B cells across the menstrual cycle and in early pregnancy, respectively, in the context of healthy women (Aim 1) and those with endometriosis and PCOS (Aim 2). Particular emphasis will be placed on regulatory lymphocytes, which include conventional CD4+ regulatory T cells (Tregs), and cells from the CD8+ T cell and B cell lineages, since these cells are likely critical for ensuring a controlled inflammatory microenvironment optimal for implantation and successful pregnancy. Since the differentiation and function of these cells can be locally influenced by non-immune endometrial and decidual cells, such as stromal fibroblasts, Aim 3 will define the role of such cells in supporting suppressive lymphocyte differentiation and identify the key regulators involved in these processes. The proposal will also determine how endometriosis and PCOS alter the phenotypes of the NK cell lineage of lymphocytes, given the contribution of NK cells to important developmental events of early pregnancy. The Aims will be accomplished using archived and prospectively collected endometrial/decidual specimens from a total of 150 well-characterized subjects. Our central hypothesis is that different lymphocyte subsets with diverse roles in immunoregulation and microbial defense work together in a coordinated fashion to establish and maintain the appropriate endometrial and decidual environment for pregnancy success, and that these cells are altered and derailed by inflammatory disorders associated with poor reproductive outcomes. Completion of this study will reveal fundamental insights into lymphocyte contributions to tolerance and can reveal new targets for diagnostics and therapeutics to improve reproductive success.

子宫内膜异位症和多囊卵巢综合征（PCOS）是女性生育力低下和不孕的主要原因。每个 伴随着由不确定的机制引发和延续的慢性子宫内膜炎症。 免疫细胞，特别是T和B淋巴细胞在子宫内膜炎症中的潜在作用主要是 尽管它们是许多其他非子宫内膜组织炎症的关键协调者和介质， contexts.此外，子宫内膜T和B细胞的抗原特异性还没有很好的描述， 尽管有证据表明，自身抗原特异性克隆导致生殖结果不良的疾病尚不清楚， 尤其是子宫内膜异位症可能有自身免疫成分。这些知识差距代表了 改善子宫内膜异位症和多囊卵巢综合征不孕患者生殖结局的机会。此外，委员会认为， 这些疾病代表了研究子宫内膜免疫失调如何 更广泛地导致不育和生育力低下。因此，本项目的目标是确定T 和B细胞有助于子宫内膜炎症的发病机制，并且通过扩展，有助于蜕膜炎症， 与着床失败和不良妊娠结局有关。在此，我们建议深入描述 频率，转录组，蛋白质组，TCR/BCR库，和抗原特异性的子宫内膜和 蜕膜T和B细胞在整个月经周期和妊娠早期，分别在健康的背景下， 女性（目标1）和子宫内膜异位症和PCOS患者（目标2）。将特别强调监管 淋巴细胞，其包括常规的CD 4+调节性T细胞（T细胞），以及来自CD 8 + T细胞和B细胞的细胞 细胞谱系，因为这些细胞可能对于确保受控的炎症微环境最佳至关重要 植入和成功怀孕。由于这些细胞的分化和功能可以在局部 受非免疫性子宫内膜和蜕膜细胞如间质成纤维细胞的影响，Aim 3将确定其作用 这些细胞在支持抑制性淋巴细胞分化中的作用，并确定参与 这些过程。该提案还将确定子宫内膜异位症和PCOS如何改变NK细胞的表型。 淋巴细胞的细胞谱系，考虑到NK细胞对早期重要发育事件的贡献， 怀孕将使用存档和前瞻性采集的子宫内膜/蜕膜 样本来自150名特征良好的受试者。我们的核心假设是不同的淋巴细胞 在免疫调节和微生物防御中具有不同作用的亚群以协调的方式一起工作， 建立和维持适当的子宫内膜和蜕膜环境，以确保妊娠成功， 这些细胞被与不良生殖结果相关的炎症性疾病改变和破坏。 这项研究的完成将揭示淋巴细胞对耐受性的贡献的基本见解， 揭示了诊断和治疗的新目标，以提高生殖成功率。