Lymphocyte function in inflammatory disorders of human endometrium and decidua

子宫内膜异位症和多囊卵巢综合征(PCOS)是女性不孕不育的主要原因。每个人 伴随着慢性子宫内膜炎，由不确定的机制触发和持续。 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组织炎症的关键协调者和介质，但仍未被研究 上下文。此外，子宫内膜T和B细胞的抗原特异性没有得到很好的描述，以及 尽管有证据表明，自身抗原特异性克隆会导致生殖结局不佳的疾病，但目前尚不清楚 尤其是子宫内膜异位症，可能与自身免疫有关。这些知识差距代表了主要的 改善子宫内膜异位症和多囊卵巢综合征不孕症患者生殖结局的机会。此外， 这些疾病是研究子宫内膜免疫失调的理想模型。 在更广泛的范围内导致不孕不育和不育。因此，该项目的目标是确定T如何 B细胞参与了子宫内膜炎症的发病，进而导致蜕膜炎症， 与植入失败和不良妊娠结局有关。在这里，我们建议深刻地描述 子宫内膜和子宫内膜的频率、转录本、蛋白质组、TCR/BCR谱系和抗原特异性 在健康的背景下，分别在月经周期和早孕期间的蜕膜T和B细胞 妇女(目标1)和子宫内膜异位症和多囊卵巢综合征患者(目标2)。将特别强调监管 淋巴细胞，包括常规的CD4+调节性T细胞(Tregs)以及来自CD8+T细胞和B细胞的细胞 细胞谱系，因为这些细胞可能是确保受控炎症微环境最佳的关键 用于植入和成功怀孕。因为这些细胞的分化和功能可以是局部的 受非免疫性子宫内膜和蜕膜细胞的影响，如间质成纤维细胞，目标3将定义其作用 这类细胞在支持抑制淋巴细胞分化中的作用，并确定参与其中的关键调节因子 这些过程。该提案还将确定子宫内膜异位症和多囊卵巢综合征如何改变NK的表型 淋巴细胞的细胞谱系，考虑到NK细胞在早期重要发育事件中的作用 怀孕了。这些目标将通过存档和预期收集的子宫内膜/蜕膜来实现 样本来自150个具有良好特征的受试者。我们的中心假设是不同的淋巴细胞 在免疫调节和微生物防御中扮演不同角色的亚群以协调的方式共同工作 为妊娠成功建立和维持适当的子宫内膜和蜕膜环境 这些细胞被与不良生殖结局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以及 揭示诊断和治疗的新目标，以提高生育成功率。

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.