McIntyre John A, Chapman Joab, Shavit Efrat, Hamilton Ronald L, Dekosky Steven T
HLA-Vascular Biology Laboratory, St Francis Hospital and Health Care Centers, Beech Grove, IN 46107, USA.
Autoimmunity. 2007 Jul;40(5):390-6. doi: 10.1080/08916930701421020.
Oxidation of cerebrospinal fluid (CSF) causes differential unmasking of autoantibodies in control CSF vs. that obtained from postmortem CSF samples from autopsy confirmed Alzheimer's disease (AD) cases. This study demonstrates that normal CSF from both living patients and from non-demented autopsy cases contains redox-reactive autoantibodies with specificities that include antiphospholipid antibodies (aPL). In contrast, CSF from autopsy confirmed AD subjects contained little or no redox-reactive aPL autoantibodies. Tests using an in vitro rat synaptosome model showed that the oxidized CSF autoantibodies from a normal individual can cause ERK1/2 phosphorylation at a level consistent with reports of pathogenic changes found in brain tissues from AD patients. The decrease or absence of redox-reactive antibodies in CSF from Alzheimer's patients suggests that these antibodies may have been previously unmasked by the oxidative conditions that exist in the CNS in AD patients. These unmasked autoantibodies could then bind to neuronal tissues and possibly participate in the initial cascade leading to the dementia in Alzheimer's. To our knowledge, this is the first description of resident autoantibodies with the potential to cause brain cell damage documented in CSF without a breech in the blood-brain barrier. The untimely and inappropriate physiological unmasking of these redox-reactive autoantibodies in AD patients CSF may represent a valuable biomarker for diagnosis and progression of this and perhaps other neurodegenerative diseases which also have oxidative stress components. These novel autoantibody observations may stimulate thoughts about additional therapeutic approaches and warrant similar studies for other neurodegenerative diseases.
脑脊液（CSF）的氧化会导致对照脑脊液与经尸检确诊为阿尔茨海默病（AD）病例的死后脑脊液样本中自身抗体的差异性暴露。本研究表明，来自活体患者和非痴呆尸检病例的正常脑脊液均含有具有多种特异性的氧化还原反应性自身抗体，其中包括抗磷脂抗体（aPL）。相比之下，经尸检确诊为AD的受试者的脑脊液中几乎不含或完全不含氧化还原反应性aPL自身抗体。使用体外大鼠突触体模型进行的测试表明，来自正常个体的氧化脑脊液自身抗体可导致ERK1/2磷酸化，其水平与AD患者脑组织中发现的致病性变化报告一致。AD患者脑脊液中氧化还原反应性抗体的减少或缺失表明，这些抗体可能先前已被AD患者中枢神经系统中存在的氧化条件所暴露。这些暴露的自身抗体随后可能与神经元组织结合，并可能参与导致阿尔茨海默病痴呆的初始级联反应。据我们所知，这是首次描述脑脊液中存在的具有导致脑细胞损伤潜力的常驻自身抗体，且血脑屏障未被破坏。AD患者脑脊液中这些氧化还原反应性自身抗体的不合时宜和不适当的生理性暴露可能是这种以及其他可能也具有氧化应激成分的神经退行性疾病诊断和病情进展的有价值生物标志物。这些关于新型自身抗体的观察结果可能会引发对其他治疗方法的思考，并为其他神经退行性疾病开展类似研究提供依据。
