Modulator of VRAC Current 1 Is a Potential Target Antigen in Multiple Sclerosis.

IF 7.8 1区医学 Q1 CLINICAL NEUROLOGY

Neurology® Neuroimmunology & Neuroinflammation Pub Date : 2025-03-01 Epub Date: 2025-02-11 DOI:10.1212/NXI.0000000000200374

Johannes Raffael Dahl, Alicia Weier, Christopher Winter, Maik Hintze, Veit Rothhammer, Thanos Tsaktanis, Anne-Katrin Proebstel, Tradite Neziraj, Elisabeth Poessnecker, Johanna Oechtering, Jens Kuhle, Boris-Alexander Kallmann, Gabriele Luber, Thorsten Heider, Luisa Klotz, Rittika Chunder, Stefanie Kuerten

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Abstract

Background and objectives: Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the CNS. Highlighted by the success of B-cell-depleting therapies such as the monoclonal anti-CD20 antibodies rituximab, ocrelizumab, and ofatumumab, B cells have been shown to play a central role in the immunopathology of the disease. Yet, the target antigens of the pathogenic B-cell response in MS remain unclear.

Methods: We combined polyclonal B-cell stimulation of peripheral blood mononuclear cells with a human proteome-wide protein microarray to identify target antigens of MS by comparing samples from 20 patients with MS with 9 age-matched and sex-matched healthy controls. Results were verified by enzyme-linked immunosorbent assay (ELISA) in 3 independent validation cohorts (N = 47 patients with MS in remission; N = 20 patients with MS during relapse; N = 25 HCs; N = 30 patients with other noninflammatory neurologic diseases; N = 9 patients with other inflammatory neurologic diseases). Experimental autoimmune encephalomyelitis (EAE) was used as an animal model to evaluate the pathogenicity of the antibodies of choice.

Results: Our results corroborate the existing concept of a highly diverse autoimmune response in MS. Yet, a significantly elevated antibody response against the membrane protein modulator of VRAC current 1 (MLC1) was noted in B-cell culture supernatants and serum samples of patients with MS. Furthermore, significantly elevated titers to MLC1 were observed in the CSF of patients with neuroinflammatory diseases other than MS. Neurons and astrocytes were identified as the main cell types expressing MLC1 in the brain of a patient with MS. Injection of anti-MLC1 antibodies into mice with EAE led to strong in vivo binding to cerebral cortical neurons and to the death of 4 of the 7 injected mice.

Discussion: Future studies will have to address the diagnostic and prognostic value of MLC1-specific antibodies in neuroinflammatory disorders such as MS and characterize the functional role of MLC1 expression in neurons and astrocytes.

Trial registration information: The study has been registered in the German Clinical Trials Register (study number DRKS00015528).

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VRAC电流1调节剂是多发性硬化症的潜在靶抗原。

背景和目的：多发性硬化症（MS）是一种慢性免疫介导的中枢神经系统脱髓鞘疾病。由于B细胞消耗疗法的成功，如单克隆抗cd20抗体利妥昔单抗、ocrelizumab和ofatumumab， B细胞已被证明在该疾病的免疫病理中发挥核心作用。然而，MS致病性b细胞反应的靶抗原仍不清楚。方法：我们将多克隆b细胞刺激外周血单个核细胞与人类蛋白质组蛋白微阵列相结合，通过比较20例多发性硬化症患者和9例年龄匹配和性别匹配的健康对照，鉴定多发性硬化症的靶抗原。结果通过酶联免疫吸附试验（ELISA）在3个独立验证队列(N = 47例缓解期MS患者；N = 20例复发期MS患者；N = 25个hc；N = 30例其他非炎症性神经系统疾病患者；N = 9例伴有其他炎性神经系统疾病)。以实验性自身免疫性脑脊髓炎（EAE）为动物模型，评价所选抗体的致病性。结果:我们的研究结果证实了ms中存在高度多样化的自身免疫反应的现有概念，然而，在ms患者的b细胞培养上清和血清样本中发现了针对VRAC电流1 （MLC1）的膜蛋白调节剂的抗体反应显著升高。在多发性硬化症以外的神经炎性疾病患者的脑脊液中，MLC1滴度显著升高。在多发性硬化症患者的大脑中，神经元和星形胶质细胞被确定为表达MLC1的主要细胞类型。将抗MLC1抗体注射到EAE小鼠体内，导致与大脑皮质神经元的强结合，并导致7只注射小鼠中的4只死亡。讨论：未来的研究必须解决MLC1特异性抗体在神经炎性疾病（如多发性硬化症）中的诊断和预后价值，并表征MLC1在神经元和星形胶质细胞中的表达的功能作用。试验注册信息：该研究已在德国临床试验注册中注册（研究号DRKS00015528）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurology® Neuroimmunology & Neuroinflammation Neuroscience-Neurology

CiteScore

15.60

自引率

2.30%

发文量

219

审稿时长

8 weeks

期刊介绍： Neurology Neuroimmunology & Neuroinflammation is an official journal of the American Academy of Neurology. Neurology: Neuroimmunology & Neuroinflammation will be the premier peer-reviewed journal in neuroimmunology and neuroinflammation. This journal publishes rigorously peer-reviewed open-access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation, affecting the full range of neurologic diseases including (but not limited to) Alzheimer's disease, Parkinson's disease, ALS, tauopathy, and stroke; multiple sclerosis and NMO; inflammatory peripheral nerve and muscle disease, Guillain-Barré and myasthenia gravis; nervous system infection; paraneoplastic syndromes, noninfectious encephalitides and other antibody-mediated disorders; and psychiatric and neurodevelopmental disorders. Clinical trials, instructive case reports, and small case series will also be featured.