Xing Hui Qin, Moritoyo Takashi, Mori Kazuyasu, Sugimoto Chie, Ono Fumiko, Izumo Shuji
Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Neuropathology. 2009 Feb;29(1):13-9. doi: 10.1111/j.1440-1789.2008.00929.x. Epub 2008 May 27.
The pathogenesis of acquired immunodeficiency syndrome dementia complex (ADC) is still poorly understood. Many studies suggest that proinflammatory cytokines such as IL-1beta and TNF-alpha released by microglia/macrophages or astrocytes play a role in CNS injury. A microscopic finding of a microglial nodule with multinucleated giant cells (MNGCs) is a histopathologic hallmark of ADC and named HIV encephalitis. However, in vivo expression of these cytokines in this microenvironment of HIV encephalitis is not yet clarified. One of the main reasons is complexities of brain pathology in patients who have died from terminal AIDS. In this study, we infected two macaques with macrophage-tropic Simian immunodeficiency virus SIV239env/MERT and examined expression of TNF-alpha and IL-1beta in inflammatory lesions with MNGCs and its relation to virus-infected cells using immunohistochemistry. One macaque showed typical inflammatory lesions with MNGCs in the frontal white matter. Small microglial nodules were also detected in the basal ganglia and the spinal cord. SIVenv positive cells were detected mainly in inflammatory lesions, and seemed to be microglia/macrophages and MNGCs based on their morphology. Expression of IL-1beta and TNF-alpha were detected in the inflammatory lesions with MNGCs, and these positive cells were found to be negative for SIVenv by double-labeling immunohistochemistry or immunohistochemistry of serial sections. There were a few TNF-alpha positive cells and almost no IL-1beta positive cells in the area other than inflammatory lesions. Another macaque showed scattered CD3+ cells and CD68+ cells in the perivascular regions of the white matter. SIVenv and TNF-alpha was demonstrated in a few perivascular macrophages. These findings indicate that virus-infected microglia/macrophages do not always express IL-1beta and TNF-alpha, which suggests an indirect role of HIV-1-infected cells in cytokine-mediated pathogenesis of ADC. Our macaque model for human ADC may be useful for better understanding of its pathogenesis.
获得性免疫缺陷综合征痴呆综合征（ADC）的发病机制仍未完全明了。许多研究表明，小胶质细胞/巨噬细胞或星形胶质细胞释放的促炎细胞因子如白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）在中枢神经系统损伤中起作用。显微镜下发现含有多核巨细胞（MNGC）的小胶质结节是ADC的组织病理学标志，称为HIV脑炎。然而，这些细胞因子在HIV脑炎这种微环境中的体内表达情况尚未阐明。主要原因之一是死于晚期艾滋病患者脑病理学的复杂性。在本研究中，我们用嗜巨噬细胞性猿猴免疫缺陷病毒SIV239env/MERT感染了两只猕猴，并使用免疫组织化学方法检测了含有MNGC的炎性病变中TNF-α和IL-1β的表达及其与病毒感染细胞的关系。一只猕猴在额叶白质出现了含有MNGC的典型炎性病变。在基底神经节和脊髓也检测到了小的小胶质结节。SIVenv阳性细胞主要在炎性病变中被检测到，根据其形态似乎是小胶质细胞/巨噬细胞和MNGC。在含有MNGC的炎性病变中检测到了IL-1β和TNF-α的表达，通过双重免疫组织化学或连续切片免疫组织化学发现这些阳性细胞SIVenv呈阴性。在炎性病变以外的区域有少数TNF-α阳性细胞，几乎没有IL-1β阳性细胞。另一只猕猴在白质的血管周围区域出现散在的CD3 +细胞和CD68 +细胞。在少数血管周围巨噬细胞中检测到SIVenv和TNF-α。这些发现表明病毒感染的小胶质细胞/巨噬细胞并不总是表达IL-1β和TNF-α，这提示HIV-1感染细胞在ADC细胞因子介导的发病机制中起间接作用。我们的人类ADC猕猴模型可能有助于更好地理解其发病机制。
