Paradigms of maintaining anterior segment homeostasis

项目摘要/摘要 眼睛中的炎症反应，如角膜损伤后，以及自身免疫介导的葡萄膜炎， 必须加以控制和解决，以保持动态平衡和防止损害。在所有这些情况下，我们 发现免疫细胞被招募到晶状体表面，许多细胞的特征与 免疫调节。晶状体的中心位置及其与大多数眼组织的界面 房水和玻璃体体液使其处于晶状体囊相关免疫的完美位置 细胞(LC-AICS)呈递抗原并产生蛋白质，可在整个过程中发挥免疫抑制功能 眼睛。此外，我们发现，有常驻免疫细胞，免疫系统的哨兵， 在发育过程中整合到晶状体中。我们现在以这些发现为基础进行研究，目的是 了解晶状体常驻免疫细胞和来自其他眼的LC-AIC的谱系和功能 它们在维持动态平衡中的作用，以及它们的长期持久性是否与致病有关 结果。在目标1中，我们将进行谱系追踪研究，以确定它们的个体发育。这些研究将 揭示这些免疫细胞群体是长寿的、自我更新的和胚胎卵黄囊来源的，还是 短命的，骨髓来源的典型的那些被招募到组织中的对损伤和发病机制的反应。 由于组织常驻免疫细胞是损伤和发病机制的直接反应者，我们将调查 它们在角膜损伤后的激活是否与LC-AIC的募集和再生有关 角膜修复术。在目标2中，我们将进行详细的免疫调节特性的分析 LC-AICS在角膜损伤后和葡萄膜炎后被招募到晶状体。这些研究将包括功能 分析直接将LC-AICS与抑制T细胞激活联系起来。我们还检查了反- 蛋白分解释放的生物活性基质衍生分子的炎症和抗血管生成特性 当LC-AICs在晶状体囊内迁移时，通过LC-AICs。我们对LC-AICS的研究有力地支持了他们 在眼睛中作为免疫调节剂的重要功能，包括我们发现它们与 葡萄膜眼炎症消退过程中的晶状体表面。然而，他们在这方面的长期坚持 晶状体囊表面超过这一时间，以及一个子集取消晶状体免疫特权和 渗入晶状体，表明它们的长期存在可能会导致病理结果。在《目标3》中，我们将 确定LC-AICS穿过晶状体囊渗入晶状体的机制及其命运， 包括它们是否可以通过成为产生I型胶原的肌成纤维细胞来促进白内障的发生。在……里面 此外，我们将研究LC-AICS维持在 晶状体表面缠绕在一起，虹膜在葡萄膜炎晚期附着，这是 可能与葡萄膜炎的病理结果有关。了解这些联系可能会导致新的治疗方法 与慢性炎症相关的眼部病变患者的选择。

Project Summary/Abstract Inflammatory responses in the eye, such as following corneal wounding, and in autoimmune-mediated uveitis, must be controlled and resolved to preserve homeostasis and prevent damage. In all these conditions, we discovered that immune cells are recruited to the surface of the lens, many with characteristics associated with immunomodulation. The central location of the lens and its interface with most eye tissues via the adjacent aqueous and vitreous humors places it in the perfect position for these Lens Capsule Associated Immune Cells (LC-AICs) to present antigens and produce proteins that can exert immunosuppressive functions across the eye. In addition, we found that there are resident immune cells, the sentinels of the immune system, that become integrated within the lens during development. We now build on these findings with studies aimed at understanding the lineage and functions of lens resident immune cells and LC-AICs recruited from other ocular sites, their roles in maintaining homeostasis, and whether their long-term persistence is linked to pathogenic outcomes. In Aim 1, we will perform lineage tracing studies to determine their ontogeny. These studies will reveal whether these immune cell populations are long-lived, self-renewing and embryonic yolk-sac derived, or short-lived, bone marrow-derived typical of those recruited to tissues in response to injury and pathogenesis. Since tissue resident immune cells are immediate responders to injury and pathogenesis, we will investigate whether their activation in response to corneal wounding is linked to LC-AIC recruitment and regenerative repair of the cornea. In Aim 2, we will perform a detailed analysis of the immunomodulatory properties of the LC-AICs recruited to the lens post-corneal wounding and in uveitis. These studies will include a functional analysis to directly link the LC-AICs to the suppression of T-cell activation. We also examine the anti- inflammatory and anti-angiogenic properties of the bioactive matrix-derived molecules proteolytically released by LC-AICs as they migrate within the lens capsule. Our studies of the LC-AICs strongly support their important functions as immunomodulators in the eye, including our discovery that they persist integrated with the lens surface during the resolution of inflammation in uveitic eyes. However, their long-term persistence at the lens capsule surface beyond this time, and the ability of a subset to abrogate lens immune privilege and infiltrate the lens, suggests that their prolonged presence could lead to pathological outcomes. In Aim 3, we will determine the mechanisms by which LC-AICs cross the lens capsule to infiltrate the lens and their fate, including whether they can be agents of cataractogenesis by becoming collagen I-producing myofibroblasts. In addition, we will investigate the properties of the fibrillar network with which the LC-AICs maintained on the surface of the lens become entwined, and to which the iris becomes attached at late stages of uveitis, which could be linked to pathological outcomes of uveitis. Understanding these links could lead to new treatment options for patients with ocular pathologies associated with chronic inflammation.