Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats
Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats
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DOI：
10.1016/j.expneurol.2012.10.013
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发表时间：
2013-01-01
影响因子：
5.3
通讯作者：
Geis, Christian
中科院分区：
文献类型：
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作者：
Hansen, Niels;Gruenewald, Benedikt;Geis, Christian
僵硬人综合征（SPS）是一种以肌肉僵硬、痉挛和焦虑为特征的自身免疫性中枢神经系统疾病。大多数患者具有抗谷氨酸脱羧酶（GAD65）的高滴度自身抗体（ab）。sps相关的IgG与ab对GAD65的致病作用已被证明与焦虑样行为有关，但与核心运动体征无关。我们在实验大鼠的侧脑室（i.c.v）或鞘内（i.th）重复注射具有严重运动障碍但无焦虑合并症的SPS患者的纯化IgG部分，其中含有高滴度的抗gad65抗体（SPS-IgG）。我们分析了对运动和类焦虑行为的影响。非sps人IgG作为对照。体外注射SPS-IgG的动物表现出僵硬样行为，行走能力受损，上肢握力下降，以及姿势和感觉运动功能障碍。对焦虑样行为的测试显示，SPS和对照组ig治疗大鼠之间没有显著差异。IgG沉积仅在SPS-IgG处理的大鼠中发现，并且主要定位于参与运动控制的中枢神经系统结构，包括苍白球、内囊、纹状体和前丘脑。双免疫荧光染色显示，以gaba能为主的间细胞对体外注射的SPS-IgG呈阳性。大鼠注射1。伴SPS-IgG的大鼠未出现明显的运动症状，脊髓水平突触传递正常。我们得出结论，高滴度抗gad65抗体的SPS患者的IgG被动转移可以诱导大鼠的SPS样运动功能障碍。与两角化蛋白抗体在SPS中观察到的结果相比，脊髓上运动通路的gab能功能障碍可能导致大鼠的运动功能障碍。(c) 2012 Elsevier Inc.版权所有。
Stiff person syndrome (SPS) is an autoimmune CNS disorder characterized by muscle rigidity, spasms and anxiety. The majority of patients have high-titer autoantibodies (ab) against glutamate decarboxylase (GAD65). A pathogenic role of SPS-associated IgG with ab against GAD65 has been shown for anxiety-like behavior but not for the core motor signs.We repetitively injected the purified IgG fraction of an SPS patient with severe motor impairment but without anxious comorbidity containing high titers of anti-GAD65 ab (SPS-IgG) into the lateral ventricle (i.c.v.) or intrathecally (i.th.) at the spinal level in experimental rats. We analyzed the effects on motor and anxiety-like behavior. Non-SPS human IgG fractions served as controls.Animals injected i.c.v. with SPS-IgG showed stiffness-like behavior with impaired walking ability and reduced grip strength of the upper limbs as well as postural and sensorimotor dysfunction. Testing for anxiety-like behavior revealed no significant differences between SPS and control IgG-treated rats. IgG deposits were found only in rats treated with SPS-IgG and were localized predominantly in CNS structures involved in motor control including globus pallidus, internal capsule, striatum and anterior thalamus. Double immunofluorescence staining revealed that predominantly GABAergic intemeurons were positive for i.c.v. injected SPS-IgG. Rats injected i.th. with SPS-IgG did not present obvious motor symptoms and had a normal synaptic transmission at the spinal level.We conclude that SPS-like motor dysfunction can be induced in rats by passive transfer of IgG from an SPS-patient with high titer of anti-GAD65 ab. GABAergic dysfunction in supraspinal motor pathways rather than in the spinal cord may lead to motor deficits observed in the rats contrasting observations made in SPS with amphiphysin antibodies. (c) 2012 Elsevier Inc. All rights reserved.