Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.
Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.
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DOI：
10.1002/ana.26482
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发表时间：
2022-12
影响因子：
11.2
通讯作者：
McKeon, Andrew
中科院分区：
文献类型：
--
作者：
Hinson, Shannon R.;Honorat, Josephe A.;Grund, Ethan M.;Clarkson, Benjamin D.;Miske, Ramona;Scharf, Madeleine;Zivelonghi, Cecilia;Al-Lozi, Muhammad Taher;Bucelli, Robert C.;Budhram, Adrian;Cho, Tracey;Choi, Ellie;Grell, Jacquelyn;Lopez-Chiriboga, Alfonso Sebastian;Levin, Marc;Merati, Melody;Montalvo, Mayra;Pittock, Sean J.;Wilson, Michael R.;Howe, Charles L.;McKeon, Andrew
我们试图确定神经元间隔蛋白自身免疫的临床意义，并评估潜在的免疫球蛋白G效应。采用间接免疫荧光法(IFA、小鼠组织和细胞)或免疫印迹法检测Septin-Igs。用活的大鼠海马神经元实验评估细胞外Septin表位的结合(和内化)。通过在多电极阵列平台上记录细胞外场电位来确定纯化的患者免疫球蛋白对小鼠皮质神经元功能的影响。在23例患者中发现了Septin-IgS。检出Septin-5-Ig G的8例患者均有小脑性共济失调，其中7例伴有明显的眼球运动障碍。同时存在Septin-7-Ig G的2例患者中有1例有额外的精神症状(冷漠、情感迟钝和自知力差)。15例患者有Septin-7自身免疫性，未检测到Septin-5-Ig G。疾病包括脑病(11例，伴发脊髓病2例，复发2例)，脊髓病3例，发作性共济失调1例。有脑病症状的患者中有6/11出现明显的精神症状(≥1表现为激越、淡漠、紧张症、思维障碍和偏执)。在获得数据的10人中，有8人(总共23人)在免疫治疗后有所改善，另有2人自发改善。患者免疫球蛋白(亚类1和2)产生的活体海马神经元的质膜染色与突触前和突触后的标记共存。由病人免疫球蛋白产生的小鼠皮质神经元谷氨酸和氨基丁酸能神经元混合培养的刺激性和爆裂性行为的减少既不是由于抗原的交联和内化，也不是由于补体的激活。Septin-Igs可预测不同的治疗反应性自身免疫性中枢神经系统疾病。活的神经元结合和患者免疫球蛋白诱导的电生理效应可能支持Septin特异性的病理生理学。据报道，Septin自身免疫是少数患者小脑性共济失调的原因。这项研究的目的是评估神经性Septin Igs(Septin-5和Septin-7)的表型相关性，并确定Septin-Igs是否具有致病潜力。Septin-5-Ig G与共济失调伴明显的多动眼运动障碍有关，Septin-7-Ig G与具有显著神经精神特征的脑病相关；这两种疾病通常都是免疫治疗的反应性疾病。与具有致病潜能的Septin-Igs一致，来自两个Septin自身免疫患者组的CSFIGs结合到活的啮齿动物神经元表面，并与多克隆Septin抗体共定位。此外，从Septin自身免疫患者血清中提纯的IgGs可减少混合培养的谷氨酸和GABA能皮质神经元的刺激性和突发性行为。在临床实践中，在免疫治疗敏感的潜在免疫球蛋白介导的自身免疫性中枢神经系统疾病的鉴别诊断中应考虑Septin自身免疫。
We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. Septin-IgGs were detected by indirect immunofluorescence assays (IFA, mouse tissue and cell based) or western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, 7 with prominent eye movement disorders. One of 2 with coexisting septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 with accompanying myelopathy, 2 were relapsing), myelopathy (3) and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6/11 with encephalopathic symptoms. Eight of 10 with data available (from 23 total) improved after immunotherapy, a further 2 spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. Septin-IgGs are predictive of distinct treatment-responsive autoimmune CNS disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. Septin autoimmunity has been reported as a cause of cerebellar ataxia in a limited number of patients. This current study purpose is to evaluate for phenotypic associations of neural septin IgGs (septin-5 and septin-7) and to establish if septin-IgGs had pathogenic potential. Septin-5-IgG is associated with ataxia with prominent hyperkinetic eye movement disorders and septin-7-IgG is associated with encephalopathy with prominent neuropsychiatric features; both disorders are often immune therapy responsiveness. Consistent with septin-IgGs having pathogenic potential, CSF IgGs from both septin autoimmune patient groups bound to the surface of live rodent neurons and colocalized with polyclonal septin antibodies. In addition, IgGs purified from serum of septin autoimmune patients decreased spiking and bursting behavior in mixed cultures of glutamatergic and GABAergic cortical neurons. In clinical practice, septin autoimmunity should be considered in the differential diagnosis of immune therapy-responsive potentially IgG mediated autoimmune CNS diseases.
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