Ocular HSV: Role of virus and IL-2 in Optic neuritis

描述：脱髓鞘疾病构成了一系列免疫病理综合征，其中髓鞘，脑、视神经和脊髓神经细胞纤维的脂肪覆盖物被破坏。与髓鞘退化相关的主要疾病之一是多发性硬化症（MS）。视觉障碍是MS的初始表现，视神经脱髓鞘引起的视神经病变（ON）是MS青壮年视觉和神经功能障碍的常见原因。ON可作为MS后续病程的早期预后因素。MS患者脑脊液和血清中IL-2水平升高，提示IL-2可能在MS病理中起作用。我们探讨了表达小鼠白细胞介素-2 （HSV-IL-2）的重组单纯疱疹病毒1型（HSV-1）感染小鼠的影响。我们的初步研究表明，通过视觉诱发皮层电位（VECPs）和尸检时的组织学检查，这种感染导致脱髓鞘。相比之下，单纯的野生型（wt） HSV感染、HSV-IL-4和HSV- ifn - γ病毒（与HSV-IL-2相同，但表达IL-4或ifn - γ而不是IL-2）感染都不会引起脱髓鞘。对脑和脊髓细胞浸润的分析表明，与感染对照病毒的小鼠相比，HSV-IL-2感染组活化T细胞和产生CD11b+的IL-12反应增强。基于我们的初步数据，我们提出了工作假设，即HSV-IL-2表达IL-2招募并激活CD8+ t细胞和巨噬细胞浸润到中枢神经系统。刺激后，CD8+ T细胞直接引起脱髓鞘，巨噬细胞通过表达IL-12和推动免疫反应向TH1反应加剧了这一过程。我们详细的具体目的是进一步阐明HSV-IL-2诱导脱髓鞘的生物学和免疫学机制，包括：1。明确hsv - il -2感染小鼠中枢神经系统脱髓鞘过程。2. 确定IL-2的产生和细胞浸润在脱髓鞘中的相对作用。3. 确定表达IL-4的重组HSV-1 （HSV-IL-4）是否可以预防hsv - il -2诱导的脱髓鞘，而表达ifn - γ的类似重组病毒则没有益处。

DESCRIPTION: Demyelinating diseases constitute a spectrum of immunopathologic syndromes in which, myelin, the fatty covering of nerve cell fibers in the brain, optic nerve, and spinal cord, is destroyed. One of the major diseases associated with degradation of the myelin sheath is multiple sclerosis (MS). Visual disturbances are initial manifestation of MS and optic neuropathy (ON) due to demyelination of optic nerve is a common cause of visual and neurologic dysfunction in young adults diagnosed with MS. ON can be used as an early prognostic factor during the subsequent course of MS. As MS patients have elevated levels of IL-2 in their CSF and sera, which suggests that IL-2 may play a role in the pathology of MS, we explored the effects of infection of mice with a recombinant herpes simplex virus type 1 (HSV-1) expressing murine interleukin-2 (HSV-IL-2). Our Preliminary Studies show that this infection results in demyelination, as determined by visual-evoked cortical potentials (VECPs) and histologic examination at autopsy. In contrast, neither wild- type (wt) HSV infection alone nor HSV-IL-4, nor HSV-IFN-gamma virus (identical to HSV-IL-2 but expressing IL-4 or IFN-gamma instead of IL-2) infection caused demyelination. Analysis of the cellular infiltrates in the brain and spinal cord indicates enhanced activated T cells and IL-12 producing CD11b+ responses in HSV-IL-2 infected group compared with mice infected with control viruses. Based on our preliminary data, we have formulated the working hypothesis that expression of IL-2 by HSV-IL-2 recruits and activates CD8+ T-cells and macrophage infiltrates to the CNS. Following stimulation the CD8+ T cells directly cause demyelination, with the macrophages exacerbating the process by expressing IL-12 and pushing the immune response toward a TH1 response. Our detailed specific aims to further elucidate the biological and immunological mechanisms responsible for HSV-IL-2 induced demyelination include: 1. Define the demyelination process in the CNS of HSV-IL-2-infected mice. 2. Determine the relative roles of IL-2 production and cellular infiltrates in demyelination. 3. Determine if a recombinant HSV-1 expressing IL-4 (HSV-IL-4) can protect against HSV-IL-2-induced demyelination, while a similarly made recombinant virus expressing IFN-gamma is not beneficial.