Corneal Lymphatics & Adaptive Immunity

正常的无血管角膜中的新生血管可导致视轴受损。 在术语“新生血管”中是一种血液成分，称为血管生成和 一种称为淋巴管生成的淋巴成分。相对于单纯疱疹病毒类型 单纯疱疹病毒1型(HSV-1)感染后，仅对血管生成进行了研究。最近，我们发起了一项 单纯疱疹病毒1型角膜感染后淋巴管生成的研究及发现 先于血管生成。更重要的是，我们发现了淋巴管的起源 角膜血管对HSV-1感染的反应通过一种独特的途径进行 与角膜移植后的描述截然不同。具体来说，我们有 发现一种强大的血管内皮生长因子(VEGF)A由角膜上皮反应 HSV-1感染血管内皮生长因子受体2(VEGFR2)介导的淋巴管生成 路径。这一过程不依赖于血管内皮生长因子C、血管内皮生长因子受体3或 单核/巨噬细胞。我们还发现，新生成的淋巴管是 能够将可溶性抗原运送到引流的淋巴结内 血管生成。然而，仍不为人所知的是新创建的 引流淋巴结内宿主免疫反应的淋巴管以及其他 促进角膜淋巴管生成的炎性介质。我们假设 淋巴管发育主要由血管内皮生长因子A驱动并参与促炎作用 局部产生的分子对感染的反应对于诱导适应性 引流淋巴结中发现的免疫反应反映了发育中的严重程度 单纯疱疹病毒1型感染小鼠的疱疹间质性角膜炎。为了解决这一假设，有两个具体的 提出目标：具体目标1将解决病毒复制的影响和促进 炎性细胞因子在单纯疱疹病毒1型感染后角膜淋巴管生成中的表达在……里面 此外，还将监测白细胞亚群和抗原的贩运。特定的 目标2将阐述淋巴管生成相对于适应性淋巴管生成的意义。 引流淋巴结的免疫反应与基质角膜炎的发生 单纯疱疹病毒1型感染。它将进一步解决病毒诱导的血管内皮生长因子A在 在病毒监测和角膜中发挥作用的CD4+和CD8+T效应细胞的产生 发病机制。预计在实现这些目标时，我们将回避以下方面的贡献 促淋巴管生成因子在产生获得性免疫反应中的作用 包括使人衰弱，有时致盲的间质角膜炎的眼部病理。

Neovascularization in the normally avascular cornea can lead to a compromised visual axis. Within the term "neovascularization" is a blood component referred to as hemangiogenesis and a lymphatic component referred to as lymphangiogenesis. Relative to herpes simplex virus type 1 (HSV-1) infection, only hemangiogenesis has been investigated. Recently, we have initiated a study on lymphangiogenesis following corneal infection with HSV-1 and discovered this process precedes hemangiogenesis. More importantly, we have discovered the genesis of lymphatic vessels in the cornea proper in response to HSV-1 infection operates thru a unique pathway distinct from what has been described following corneal transplantation. Specifically, we have found a robust vascular endothelial growth factor (VEGF) A response by corneal epithelium infected with HSV-1 elicits lymphangiogenesis thru a VEGF receptor 2 (VEGFR2)-mediated pathway. This process is independent of VEGF C, VEGF receptor 3, or monocytes/macrophages. We have also found the newly created lymphatic vessels are capable of transporting soluble antigen to the draining lymph node independent of hemangiogenesis. However, what remains unknown is the contribution of the newly created lymphatic conduit to the host immune response within the draining lymph node as well as other inflammatory mediators that contribute to corneal lymphangiogenesis. We hypothesize lymphatic vessel development driven principally by VEGF A and contributing pro-inflammatory molecules generated locally in response to infection are critical for the induction of the adaptive immune response found in the draining lymph node reflected by the severity in the development of herpetic stromal keratitis of HSV-1 infected mice. To address this hypothesis, two specific aims are proposed: Specific aim 1 will address the impact of viral replication and pro- inflammatory cytokine expression on corneal lymphangiogenesis following HSV-1 infection. In addition, trafficking of leukocyte subpopulations and antigen will be monitored as well. Specific aim 2 will address the significance of lymphangiogenesis relative to the genesis of the adaptive immune response in the draining lymph node and development of stromal keratitis following HSV-1 infection. It will further address the role of virus-induced VEGF A production on the production of CD4+ and CD8+ T effector cells that contribute in viral surveillance and corneal pathogenesis. It is anticipated in accomplishing these goals, we will eludicate the contribution of pro-lymphangiogenesis factors in the generation of the adaptive immune response critical for the ocular pathology that includes the debilitating and sometimes blinding stromal keratitis.