Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy.
Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy.
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肌醇1,4,5-三磷酸受体1型自身抗体在副塑性和非偏型外周神经病中。
DOI：
10.1186/s12974-016-0737-x
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发表时间：
2016-10-24
影响因子：
9.3
通讯作者：
Aktas O
中科院分区：
文献类型：
--
作者：
Jarius S;Ringelstein M;Haas J;Serysheva II;Komorowski L;Fechner K;Wandinger KP;Albrecht P;Hefter H;Moser A;Neuen-Jacob E;Hartung HP;Wildemann B;Aktas O
最近，我们描述了一种新的自身抗体，抗Sj/ITPR 1-IgG，其靶向小脑共济失调患者的1型肌醇1，4，5-三磷酸受体（ITPR 1）。然而，ITPR 1不仅在浦肯野细胞中表达，而且在脊髓前角、胶状质、运动、感觉（包括背根神经节）和自主周围神经系统中表达，这表明与ITPR 1自身免疫相关的临床谱可能比最初认为的更广。在这里，我们报告血清自身抗体ITPR 1（高达1：15,000）在3例（神经根）多发性神经病，其中2例与癌症（ITPR 1表达腺癌的肺，多发性骨髓瘤），这表明一个副肿瘤病因。血清学和其他免疫学研究，以及患者病历的回顾性分析。临床表现包括运动、感觉（包括剧烈疼痛）和自主神经症状。1例患者出现类似格林-巴利综合征（GBS）的亚急性症状，另外2例患者的症状进展缓慢。电生理检查显示F波延迟;运动和感觉动作电位和传导速度降低;运动延迟;去神经支配体征，表明混合型感觉运动神经根性多神经病;无传导阻滞。ITPR 1-IgG属于补体激活IgG 1亚类的严重影响的患者，但专门的IgG 2亚类的两个更轻度影响的患者。发现脑脊液ITPR 1-IgG主要来源于鞘外。基于3 H-胸苷的增殖试验证实了外周血单核细胞（PBMC）中存在ITPR 1反应性淋巴细胞。PBMC蛋白的免疫表型分析表明，用纯化的ITPR 1蛋白刺激后，B细胞、CD 4 T细胞和CD 8记忆T细胞的增殖占优势。患者ITPR 1-IgG与外周神经组织和肺肿瘤组织结合。神经活检显示淋巴细胞浸润（包括细胞毒性CD 8细胞）、水肿、明显轴突丢失和髓鞘阳性巨噬细胞，表明炎症明显。肿瘤切除后ITPR 1-IgG血清滴度下降，临床稳定。我们的研究结果扩大了与ITPR 1-IgG相关的临床综合征的范围，并表明对ITPR 1的自身免疫可能是某些患者周围神经系统疾病（包括GBS）的基础，并且在一部分病例中可能是副肿瘤起源。本文的在线版本（doi：10.1186/s12974-016-0737-x）包含补充材料。
Recently, we described a novel autoantibody, anti-Sj/ITPR1-IgG, that targets the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in patients with cerebellar ataxia. However, ITPR1 is expressed not only by Purkinje cells but also in the anterior horn of the spinal cord, in the substantia gelatinosa and in the motor, sensory (including the dorsal root ganglia) and autonomic peripheral nervous system, suggesting that the clinical spectrum associated with autoimmunity to ITPR1 may be broader than initially thought. Here we report on serum autoantibodies to ITPR1 (up to 1:15,000) in three patients with (radiculo)polyneuropathy, which in two cases was associated with cancer (ITPR1-expressing adenocarcinoma of the lung, multiple myeloma), suggesting a paraneoplastic aetiology. Serological and other immunological studies, and retrospective analysis of patient records. The clinical findings comprised motor, sensory (including severe pain) and autonomic symptoms. While one patient presented with subacute symptoms mimicking Guillain-Barré syndrome (GBS), the symptoms progressed slowly in two other patients. Electrophysiology revealed delayed F waves; a decrease in motor and sensory action potentials and conduction velocities; delayed motor latencies; signs of denervation, indicating sensorimotor radiculopolyneuropathy of the mixed type; and no conduction blocks. ITPR1-IgG belonged to the complement-activating IgG1 subclass in the severely affected patient but exclusively to the IgG2 subclass in the two more mildly affected patients. Cerebrospinal fluid ITPR1-IgG was found to be of predominantly extrathecal origin. A 3H-thymidine-based proliferation assay confirmed the presence of ITPR1-reactive lymphocytes among peripheral blood mononuclear cells (PBMCs). Immunophenotypic profiling of PBMCs protein demonstrated predominant proliferation of B cells, CD4 T cells and CD8 memory T cells following stimulation with purified ITPR1 protein. Patient ITPR1-IgG bound both to peripheral nervous tissue and to lung tumour tissue. A nerve biopsy showed lymphocyte infiltration (including cytotoxic CD8 cells), oedema, marked axonal loss and myelin-positive macrophages, indicating florid inflammation. ITPR1-IgG serum titres declined following tumour removal, paralleled by clinical stabilization. Our findings expand the spectrum of clinical syndromes associated with ITPR1-IgG and suggest that autoimmunity to ITPR1 may underlie peripheral nervous system diseases (including GBS) in some patients and may be of paraneoplastic origin in a subset of cases. The online version of this article (doi:10.1186/s12974-016-0737-x) contains supplementary material.
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影响因子：
9.3
作者：
Jarius S;Scharf M;Begemann N;Stöcker W;Probst C;Serysheva II;Nagel S;Graus F;Psimaras D;Wildemann B;Komorowski L
通讯作者：
Komorowski L
影响因子：
6.4
作者：
Jarius, Sven;Wildemann, Brigitte
通讯作者：
Wildemann, Brigitte
影响因子：
11
作者：
Jarius, S.;Franciotta, D.;Voltz, R.
通讯作者：
Voltz, R.
影响因子：
4.4
作者：
GRAUS, F;ILLA, I;JUAREZ, C
通讯作者：
JUAREZ, C
影响因子：
9.9
作者：
Balint, Bettina;Jarius, Sven;Meinck, Hans-Michael
通讯作者：
Meinck, Hans-Michael