Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
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DOI：
10.1093/brain/awq213
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Vincent A
中科院分区：
文献类型：
--
作者：
Irani SR;Alexander S;Waters P;Kleopa KA;Pettingill P;Zuliani L;Peles E;Buckley C;Lang B;Vincent A
从哺乳动物脑组织中提取的125 I-α-树突状毒素标记的电压门控钾通道的免疫沉淀抗体已在神经性肌强直、Morvan综合征、边缘系统脑炎和少数成人发作性癫痫患者中鉴定。这些疾病通常在免疫调节治疗后得到改善。然而，不同综合征的比例、相关肿瘤的数量以及与钾通道亚单位抗体特异性的关系尚不清楚。我们记录了96例钾通道抗体阳性患者（滴度>400 pM）的临床表型和肿瘤相关性。5例为胸腺瘤，1例为子宫内膜腺癌。为了确定抗体特异性，我们使用表达钾通道亚基的人胚肾细胞寻找血清抗体的结合及其对钾通道电流的影响。令人惊讶的是，只有三名患者有针对钾通道亚基的抗体。相比之下，我们在脑提取物中发现了与125 I-α-树突毒素标记的钾通道复合的三种蛋白质的抗体：（i）接触素相关蛋白-2，位于有髓鞘轴突的海马;（ii）富含亮氨酸的胶质瘤失活蛋白，在海马中表达最强;（iii）与接触素相关蛋白-2相关的Tag-1/contactin-2。在3份血清中发现了Kv 1亚基抗体，在19份血清中发现了接触素相关蛋白-2抗体，在55份血清中发现了富含亮氨酸的胶质瘤失活蛋白1抗体，在5份血清中发现了接触素-2抗体，其中4份血清对其他抗体也呈阳性。其余18例血清钾通道亚单位和相关蛋白阴性。在19例接触素相关蛋白抗体2阳性的患者中，10例有神经性肌强直或Morvan综合征，而在55例富含亮氨酸的胶质瘤失活蛋白抗体阳性的患者中，只有3例有边缘系统脑炎（P < 0.0001）。对免疫调节治疗的反应，定义为修改后的兰金评分的变化，是良好的，除了肿瘤患者，谁都有接触相关蛋白2抗体。这项研究证实，大多数高钾通道抗体的患者患有无肿瘤的边缘系统脑炎。鉴定富含亮氨酸的胶质瘤失活蛋白1和接触素相关蛋白2作为钾通道抗体的主要靶点，以及它们与不同临床特征的相关性，开始解释这些综合征的多样性;此外，检测接触素相关蛋白2抗体应有助于确定潜在肿瘤的风险和未来患者的不良预后。
Antibodies that immunoprecipitate 125I-α-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with 125I-α-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.
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DOI：
10.1093/brain/awq113
发表时间：
2010-06
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Irani SR;Bera K;Waters P;Zuliani L;Maxwell S;Zandi MS;Friese MA;Galea I;Kullmann DM;Beeson D;Lang B;Bien CG;Vincent A
通讯作者：
Vincent A
影响因子：
9.9
作者：
Graus F;Saiz A;Lai M;Bruna J;López F;Sabater L;Blanco Y;Rey MJ;Ribalta T;Dalmau J
通讯作者：
Dalmau J
影响因子：
9.9
作者：
McKnight, K;Jiang, Y;Lang, B
通讯作者：
Lang, B
影响因子：
16.2
作者：
Poliak, S;Gollan, L;Peles, E
通讯作者：
Peles, E
影响因子：
9.9
作者：
Antozzi, C;Frassoni, C;Mantegazza, R
通讯作者：
Mantegazza, R