The role of high endothelial venules in sex dimorphism in rheumatoid arthritis

总结/摘要： 这项研究提出了类风湿性关节炎性别差异的机制，特别是，我们关注 高内皮微静脉及其在女性偏向性疾病发展中的作用。 风湿性关节炎（RA）是世界范围内最常见的炎性关节病， 复杂和异质性自身免疫性疾病。治疗主要侧重于抑制过剩 炎症和减缓疾病进展，以尽量减少关节损伤和增强身体功能， 生活质量风湿性关节炎是无法治愈的。复杂的免疫调节异常导致 自身反应性炎症反应，导致持续性炎症和关节破坏。我是一个很好的- 已知的女性偏向性疾病（3：1的比例）。女性易感性高，发病早，症状重， 和更严重的疾病进展。有趣的是，青少年特发性关节炎，其中性激素是 可以忽略不计，也显示了女性偏见的疾病患病率，阐明了遗传易感性， 类风湿性关节炎大多数研究集中在激素的影响和失调 免疫细胞的遗传倾向。然而，组织微环境对性的贡献 分歧仍然难以确定。特别是，血管是白细胞最重要的通道， 迁移到关节滑膜中。对血管的研究将揭示未知的机制 对疾病发展和女性在类风湿关节炎中的偏见。 本项目将集中在异位高内皮微静脉（HEVs），专门的血管白细胞 在RA中发现但在骨关节炎中未发现募集。HEV在启动 通过募集幼稚白细胞在次级淋巴器官中获得性免疫。以前的单细胞数据 HEV显示潜在的偏斜X-失活和X-连锁基因的上调。由于剂量 在胚胎发育的补偿，一个X染色体在女性是沉默的。15-23%的X- 连锁的人类基因逃避这种X-失活，导致X-连锁基因的上调。我们将采取两 独立的方法来调查是否HEVs和他们的偏斜X失活是性别偏见的主要原因 在RA中。目的1：研究RA患者HEVs中X染色体失活和X连锁基因的表达。 目的2：在动物模型中进行概念验证研究，以证明性别二态性的原因。 本项目旨在研究HEV中的X连锁基因，并寻求其潜在的影响 女性偏好的类风湿性关节炎进展这些研究还将揭示X-失活和双等位基因表达 异位HEV中。我们的新小鼠模型进行概念验证研究是有用的，为未来的调查 研究非循环局部组织中偏斜X-失活对性二型的意义， RA.

Summary/Abstract: The proposed study addresses the mechanisms of sex differences in rheumatoid arthritis; in particular, we focus on the high endothelial venules and their roles in female-biased disease development. Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide, and it is a chronic, complex, and heterogeneous autoimmune disease. The treatment mainly focuses on suppressing excess inflammation and slowing the disease progression to minimize joint damage and enhance physical function and quality of life. There's no cure for rheumatoid arthritis. The complex abnormal regulation of immunity causes auto-reactive inflammatory reactions, leading to persistent inflammation and articular destruction. RA is a well- known female-biased disease (3:1 ratio). Women have higher susceptibility, earlier onset, severer symptoms, and more exacerbated disease progression. Interestingly, juvenile idiopathic arthritis which sex hormones are negligible, also shows a female-biased disease prevalence, illuminating the genetic predispositions in rheumatoid arthritis in females. The majority of research focuses on the hormonal influences and dysregulation of immune cells caused by genetic disposition. Yet, the contribution of the tissue microenvironment to sex differences has remained elusive. In particular, blood vessels are the most critical gateway for the leukocytes to migrate into the joint synovial membrane. Research on the blood vessels will uncover the unknown mechanism for the disease development and female biases in RA. This project will focus on ectopic high endothelial venules (HEVs), specialized vessels for leukocyte recruitment which have been found in RA but not in osteoarthritis. HEVs play a critical role in the initiation of adaptive immunity in secondary lymphoid organs by recruiting naïve leukocytes. Previous single-cell data of HEVs shows the potential skewed X-inactivation and upregulation of X-linked genes. As a result of dose compensation at embryonic development, one X-chromosome in females is silenced. However, 15-23% of X- linked human genes escape from this X-inactivation, causing upregulation of X-linked genes. We will take two independent approaches to investigate if HEVs and their skewed X-inactivation are the major cause of sex bias in RA. Aim 1: To identify the skewed X-inactivation and upregulation of X-linked genes in HEVs in human RA. Aim 2: To perform a proof-of-concept study in animal models to demonstrate the cause of sex dimorphisms. This proposed project initiates investigating the X-linked genes in HEVs and seeking their potential impact on female-biased RA progression. The studies will also uncover the X-inactivation and bi-allelic gene expression in ectopic HEVs. Our new mouse models to perform a proof-of-concept study are useful for future investigation to examine the significance of skewed X-inactivation in non-circulating local tissues for sexual dimorphisms in RA.