MOLECULAR NEUROPATHOLOGY OF AIDS ENCEPHALITIS

大约三分之一的艾滋病患者会患上临床痴呆(AIDS 痴呆症复合体，ADC)。许多临床症状都是 归因于皮质下白质和灰质的病理变化。 尽管如此，放射学研究和我们的初步病理 观察表明，严重的皮质萎缩被忽视了。 我们建议描述皮质萎缩的范围和分布。 在已故艾滋病患者的大脑中。我们将把这种萎缩联系起来 除了病理上的发现外，还有临床和放射学的发现 携带和不携带HIV的艾滋病患者更明显的皮质下改变 脑炎。我们会将皮质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 特定大小类神经元的参与。通过量化 免疫细胞化学和免疫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 突触素和脑血影素样染色增加可作为脑肿瘤的标志物 我们将把这些测量结果与形态、临床进行比较 以及皮质萎缩的放射学证据。 因为许多这些皮质和皮质下的变化都发生在HIV 感染的大脑仅限于没有可检测到的逆转录病毒蛋白或 核酸，我们假设它们是间接的而不是直接的 感染的影响，可能是由免疫因素介导的。我们将研究 特异性中枢神经系统内免疫因子在调节皮质和神经系统损伤中的作用 皮质下损伤。与其他病毒性脑炎不同，携带艾滋病毒的大脑 脑炎几乎没有体液或细胞免疫反应的证据。 然而，有数量可变的小胶质细胞/巨噬细胞(首选 HIV感染的靶点和突触重构的重要因素) 艾滋病患者的大脑。通常情况下，MHC I类表达是受限的 对内皮细胞的作用，但未观察到II类分子的表达 巨噬细胞、星形胶质细胞和内皮细胞，而II类表达 除巨噬细胞、星形胶质细胞和内皮细胞外未观察到 一种免疫反应。因为在有效免疫中至关重要的MHC抗原 在病毒感染或暴露于细胞因子期间，反应被放大， 它们在痴呆患者中枢神经系统中的存在增加的文献记录 将是病毒或免疫紊乱的敏感指标。我们会 描述巨噬细胞或神经细胞(如星形胶质细胞)的作用 产生细胞因子，介导中枢神经系统损伤。因为中枢神经系统损伤可能发生 在艾滋病患者的大脑中检测到病毒的时候 脑实质1，我们将使用商业ELISA试剂盒来量化和 比较细胞因子(IL-1β、IL-2、IL-6、肿瘤坏死因子)水平 这些尸检的血清和脑脊液中的肿瘤坏死因子和干扰素)。 因为这些细胞因子的生物半衰期很短，可以 在中枢神经系统内产生的，我们将使用免疫过氧化物酶和原位- 死后组织杂交法检测病毒的分布 尸检脑组织中的细胞因子并比较其原位分布 与神经病变的分布有关。

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.