MOLECULAR NEUROPATHOLOGY OF AIDS ENCEPHALITIS

大约三分之一的艾滋病患者发展为临床痴呆（AIDS 痴呆综合征，ADC）。 许多临床症状已经 归因于皮质下白色和灰质的病理变化。 尽管如此，放射学研究和我们的初步病理检查 观察结果表明，显著的皮质萎缩被忽视了。 我们建议描述皮质萎缩的程度和分布 艾滋病患者的大脑中 我们会把这种萎缩 除了病理学上的临床和放射学发现外， 有无HIV感染的艾滋病患者的皮质下改变更明显 脑炎 我们将皮层厚度与细胞计数相关联， 确定哪些区域表现出萎缩，以及是否存在选择性 参与特定大小的神经元。 与定量 免疫细胞化学和蛋白质印迹，我们将检查皮质突触 复杂性作为皮质损伤的敏感指标。 使用减少 突触素和增加的脑血影蛋白样染色作为 我们将这些测量结果与形态学、临床 和放射学上的皮质萎缩 因为许多这些皮层和皮层下的变化都发生在艾滋病病毒 受感染的大脑中有有限的或无法检测到的逆转录病毒蛋白， 核酸，我们假设它们是间接的，而不是直接的， 感染的影响，可能由免疫因素介导。 我们将研究 特异性CNS内免疫因子在介导皮质和 皮层下损伤 与其他病毒性脑炎不同，感染艾滋病毒的大脑 脑炎几乎没有体液或细胞免疫应答证据。 然而，存在可变数量的小胶质细胞/巨噬细胞（优选的微胶质细胞/巨噬细胞）。 HIV感染靶点和突触重塑的重要因素）， 艾滋病患者的大脑 正常情况下，MHC I类分子的表达受到限制， 而II类表达没有观察到，除了 巨噬细胞、星形胶质细胞和内皮细胞，而II类表达是 除巨噬细胞、星形胶质细胞和内皮细胞外， 免疫反应 由于MHC抗原在有效的免疫中至关重要， 在病毒感染或暴露于细胞因子期间， 记录其在痴呆病例的CNS中的存在增加 将是病毒或免疫扰动的敏感指标。 我们将 表征巨噬细胞或神经细胞（例如星形胶质细胞）的作用 产生介导CNS损伤的细胞因子。 因为中枢神经系统损伤 当艾滋病患者的大脑中检测到o病毒时， 脑实质1，我们将使用商业ELISA试剂盒定量， 比较细胞因子（IL-1 β、IL-2、IL-6、肿瘤坏死因子）水平 (TNF)和γ-干扰素）。 因为这些细胞因子具有短的生物半衰期， 在中枢神经系统内产生，我们将采用免疫过氧化物酶和原位- 在死后组织上进行杂交，以评估 细胞因子在尸体解剖的大脑中，并比较这种原位分布 与神经病理改变的分布有关。

Approximately one third of AIDS patients develop clinical dementia (AIDS dementias complex, ADC). Many of the clinical symptoms have been attributed to pathologic changes in the subcortical white and grey matter. Nevertheless, radiologic studies and our preliminary pathologic observations suggest that significant cortical atrophy has been overlooked. We propose to characterize the extent and distribution of cortical atrophy in the brain of deceased AIDS patients. We will correlate this atrophy with clinical and radiologic findings in addition to the pathologically more apparent subcortical changes in AIDS patients with and without HIV encephalitis. We will correlate cortical thickness with cell counts to identify which regions demonstrate atrophy and whether there is selective involvement of specific size class neurons. With quantitative immunocytochemistry and western blots we will examine cortical synaptic complexity as a sensitive indicator of cortical damage. Using decreased synaptophysin and increased brain spectrin-like staining as markers of synaptic loss we will compare these measurements with morphologic, clinical and radiologic evidence of cortical atrophy. Because many of these cortical and subcortical changes are occurring in HIV infected brains with limited to no detectable retroviral proteins or nucleic acids, we hypothesize that they are indirect rather than direct affects of infection, perhaps mediated by immune factors. We will examine the role of specific intra-CNS immune factors in mediating cortical and subcortical damage. Unlike other viral encephalitides, brains with HIV encephalitis show little evidence of humoral or cellular immune response. However, there are a variable number of microglia/ macrophages (a preferred target of HIV infection and an important factor in synapse remodeling) in the brains of AIDS patients. Normally MHC class I expression is restricted to endothelial cells while class II expression is not observed except on macrophages, astrocytes and endothelial cells while class II expression is not observed except on macrophages, astrocytes and endothelial cells during an immune response. Since MHC antigens critical in an effective immune response are amplified during viral infections or exposure to cytokines, documentation of their increased presence within the CNS of dementia cases will be a sensitive indicator of viral or immune perturbation. We will characterize the role of macrophage or neural cell (e.g. astrocyte) produced cytokines in mediating CNS damage. Because CNS damage can occur within AIDS patients' brains at a time when o virus is detectable within the brain parenchyma1, we will use commercial ELISA kits to quantify and compare levels of cytokines (IL-1beta, IL-2, IL-6, tumor necrosis factor (TNF), and gamma-interferon) in the serum and CSF from these autopsies. Because these cytokines have a short biological half-life and can be produced within the CNS, we will employ immunoperoxidase and in situ- hybridization on the post-mortem tissue to evaluate the distribution of the cytokines within autopsied brains and compare this in situ distribution with the distribution of neuropathologic changes.