Experimental destruction of substantia nigra initiated by Parkinson disease immunoglobulins
Experimental destruction of substantia nigra initiated by Parkinson disease immunoglobulins
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DOI：
10.1001/archneur.55.8.1075
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发表时间：
1998-08-01
影响因子：
--
通讯作者：
Appel, SH
中科院分区：
文献类型：
--
作者：
Chen, SD;Le, WDD;Appel, SH
背景：自由基和氧化应激水平的升高可能与帕金森病（PD）黑质（SN）损伤的发病机制有关，但大多数病例的起始病因尚不明确。目的：为了确定免疫机制在触发或放大神经元损伤中的潜在重要性，我们检测了PD患者的血清样本，以确定IgG在体内启动相对特异性SN损伤的能力。方法：将5例PD患者和10例DC患者血清中纯化的IgG注射于成年大鼠SN右侧。在立体定向注射水平上从全脑切下冠状面切片，用酪氨酸羟化酶和甲酚紫染色，在注射和对侧相同的脑区计数细胞谱。将相应注射区和未注射区细胞剖面计数的比值作为内标。结果：注射IgG后4周，与同一动物的对侧相比，注射侧酪氨酸羟化酶阳性细胞谱下降50%。同样，应用DC IgG仅导致18%的下降。甲酚紫染色显示，与对侧未注射侧相比，注射PD IgG的SN侧致密部神经元谱减少35%，而DC IgG的神经元谱减少10%。即使在注射PD IgG后4周，受损的SN pars致密神经元附近也出现血管周围炎症和明显的小胶质细胞浸润。立体定向注射内侧间隔区后，PD IgG对胆碱乙酰转移酶阳性神经元无细胞毒作用。中脑膜和蛋白A琼脂糖凝胶珠吸收PD IgG可去除细胞毒性，而肝膜吸收PD IgG不改变细胞毒性。结论：我们的数据表明PD IgG可以在体内启动相对特异性的致密神经元炎症破坏，并证明PD免疫机制的潜在相关性。
Background: Increased levels of free radicals and oxidative stress may contribute to the pathogenesis of substantia nigra (SN) injury in Parkinson disease (PD),but the initiating etiologic factors remain undefined in most cases.Objective: To determine the potential importance of immune mechanisms in triggering or amplifying neuronal injury, we assayed serum samples from patients with PD to determine the ability of IgG to initiate relatively specific SN injury in vivo.Methods: IgG purified from the serum of 5 patients with PD and 10 disease control (DC) patients was injected into the right side of the SN in adult rats. Coronal sections were cut from the whole brain at the level of the stereotaxic injections, stained for tyrosine hydroxylase and with cresyl violet, and cellular profiles were counted in identical brain regions at the injection and contralateral sides. The ratio of cell profile counts of the corresponding injected and uninjected regions was used as an internal standard.Results: Four weeks following injection of IgG, a 50% decrease in tyrosine hydroxylase-positive cellular profiles was noted on the injected sides compared with the contralateral sides of the same animals. Similarly, applied DC IgG caused only an 18% decrease. Cresyl violet staining revealed a 35% decrease in neuronal profiles of PD IgG injected into the SN pars compacta compared with the contralateral uninjected side, whereas DC IgG caused a minimal 10% decrease. Even at 4 weeks after the PD IgG injections, perivascular inflammation and significant microglial infiltration were present near injured SN pars compacts neurons. No cytotoxic effects of PD IgG were noted in choline acetyltransferase-positive neurons after stereotaxic injections into the medial septal region. Absorption of PD IgG with mesencephalic membranes and protein A agarose gel beads removed cytotoxicity, while absorption with liver membranes did not change the cytotoxicity.Conclusions: Our data suggest that PD IgG can initiate a relatively specific inflammatory destruction of SN pars compacta neurons in vivo and demonstrate the potential relevance of immune mechanisms in PD.