Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia.
Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia.
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DOI：
10.1186/s12974-014-0206-3
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发表时间：
2014-12-11
影响因子：
9.3
通讯作者：
Komorowski L
中科院分区：
文献类型：
--
作者：
Jarius S;Scharf M;Begemann N;Stöcker W;Probst C;Serysheva II;Nagel S;Graus F;Psimaras D;Wildemann B;Komorowski L
我们报告与小脑共济失调相关的血清自身抗体。对4名患者的血清进行自身抗体检测的免疫组织化学研究显示，高滴度（高达1：5，000）IgG抗体（主要为IgG 1）与小鼠、大鼠、猪和猴小脑切片上的分子层、浦肯野细胞层和白色物质结合。抗体结合PC胞体、树突和轴突，导致与抗Ca/抗ARHGAP 26报告的结合模式相似的结合模式，但不与重组ARHGAP 26反应。进行了广泛的对照研究，以排除先前描述的一系列副肿瘤和非副肿瘤抗神经自身抗体。特征性结合模式以及双染色实验表明，1，4，5-三磷酸肌醇受体1（ITPR 1）为靶抗原。抗原的验证包括用ITPR 1（而不是ARHGAP 26）预吸附后组织反应的特异性中和和用纯化的ITPR 1蛋白进行的斑点印迹测定。相反，抗ARHGAP 26阳性血清不与ITPR 1结合。在一个平行的方法中，组织免疫沉淀和质谱的组合也确定ITPR 1作为靶抗原。最后，使用分别表达ITPR 1和ARHGAP 26的HEK 293细胞进行的基于重组细胞的免疫荧光测定证实了ITPR 1的鉴定。ITPR 1的突变先前已经与伴有和不伴有认知能力下降的脊髓小脑性共济失调有关。我们的研究结果表明，ITPR 1自身免疫在自身免疫性小脑炎发病机制中的作用，并扩展了该疾病的诊断标志物。
We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease.
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影响因子：
6.4
作者：
Jarius, Sven;Wildemann, Brigitte
通讯作者：
Wildemann, Brigitte
影响因子：
4.4
作者：
GRAUS, F;ILLA, I;JUAREZ, C
通讯作者：
JUAREZ, C
影响因子：
11.2
作者：
de Graaff, Esther;Maat, Peter;Smitt, Peter Sillevis
通讯作者：
Smitt, Peter Sillevis
影响因子：
11
作者：
Graus, F;Delattre, JY;Voltz, R
通讯作者：
Voltz, R
影响因子：
11.2
作者：
Coesmans, M;Smitt, PAS;De Zeeuw, CI
通讯作者：
De Zeeuw, CI