Journal of neuroimmunology最新文献_第2页

Antibodies in Creutzfeldt-Jakob disease: A systematic review of patient characteristics, diagnostics, and clinical implications 克雅氏病的抗体：对患者特征、诊断和临床意义的系统回顾。

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-14 DOI: 10.1016/j.jneuroim.2026.578865

Raluca Bilavu , Marius Benta , Amalia Cornea , Lucian Vasiluta , Elena Cecilia Rosca

Background

Creutzfeldt–Jakob disease (CJD) is a rare, rapidly progressive prion neurodegenerative disorder causing fatal dementia. Recently, reports have identified various autoantibodies in confirmed CJD patients, raising questions about their significance. We performed a scoping review of published CJD cases with co-occurring antibodies, including antineuronal (e.g., NMDAR, LGI1, CASPR2, VGKC, GAD65, GlyR), anti-thyroid peroxidase, antinuclear, and infection-related antibodies, to characterize patient demographics, clinical and diagnostic features, and outcomes, and explore the pathophysiological implications of this association.

Methods

We searched PubMed and Scopus databases up to June 2024, following a published protocol. We included definite/probable CJD cases in which serum/CSF testing detected autoantibodies. Demographic information, clinical presentations, diagnostic findings, treatments, and outcomes were analyzed.

Results

We identified 65 CJD patients with co-occurring antibodies and reported an additional case of a 58-year-old woman with genetic CJD and co-existing anti-TPO and weakly positive CASPR2 antibodies. The median age was 61 years (range 28–82), with NMDAR-Ab patients older and LGI1/CASPR2-Ab cases younger. Most were diagnosed with sporadic CJD (86%) and confirmed by CJD biomarkers (RT-QuIC 100%, 14–3-3 92.6%, Tau 91.7%). Antibodies were mainly found in serum (87.2% vs. 29.8% in CSF). Rapidly progressive dementia was universal, with gait impairment (71.9%) and movement disorders (59.4%) being common. Most cases showed no improvement with immunotherapy, indicating that antibodies may be an epiphenomenon. However, a few cases had transient or partial improvement, suggesting a possible modulatory role or dual pathology.

Conclusion

Antibodies are increasingly noted in CJD as a secondary effect of neurodegeneration. They complicate diagnosis and rarely suggest treatable aspects of the disease. More research is needed to clarify their complex role.

背景：克雅氏病（Creutzfeldt-Jakob disease， CJD）是一种罕见的、进展迅速的朊病毒性神经退行性疾病，可导致致死性痴呆。最近，有报道在确诊的克雅氏病患者中发现了各种自身抗体，对其意义提出了疑问。我们对已发表的CJD共发生抗体的病例进行了范围综述，包括抗神经元抗体（如NMDAR、LGI1、CASPR2、VGKC、GAD65、GlyR）、抗甲状腺过氧化物酶、抗核抗体和感染相关抗体，以表征患者人口统计学特征、临床和诊断特征以及结果，并探讨这种关联的病理生理意义。方法：我们检索PubMed和Scopus数据库，截至2024年6月，遵循已发表的协议。我们纳入了血清/脑脊液检测检测到自身抗体的确诊/疑似CJD病例。分析了人口统计信息、临床表现、诊断结果、治疗方法和结果。结果：我们确定了65例CJD患者同时存在抗体，并报告了另外一例58岁女性遗传性CJD患者同时存在抗tpo和弱阳性CASPR2抗体。中位年龄为61岁（28-82岁），NMDAR-Ab患者年龄较大，LGI1/CASPR2-Ab患者年龄较小。大多数诊断为散发性CJD(86%)，并通过CJD生物标志物（RT-QuIC 100%, 14-3-3 92.6%, Tau 91.7%）确诊。抗体主要存在于血清中（87.2% vs. CSF 29.8%）。快速进展性痴呆是普遍的，步态障碍（71.9%）和运动障碍（59.4%）是常见的。大多数病例显示免疫治疗没有改善，表明抗体可能是一种附带现象。然而，少数病例有短暂或部分改善，提示可能的调节作用或双重病理。结论：抗体作为神经退行性变的继发效应在克雅氏病中越来越受到关注。它们使诊断复杂化，很少提示疾病的可治疗方面。需要更多的研究来阐明它们的复杂作用。

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引用次数: 0

Serum from patients with acetylcholine receptor antibody–positive myasthenia gravis triggers pathogenic changes in human myotube cells 乙酰胆碱受体抗体阳性重症肌无力患者血清引发人肌管细胞的致病性改变

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-21 DOI: 10.1016/j.jneuroim.2026.578871

Keisuke Tanaka , Akiyuki Uzawa , Manato Yasuda , Yosuke Onishi , Hiroyuki Akamine , Hideo Handa , Etsuko Ogaya , Shota Miyake , Masayuki Baba , Hiroto Abe , Koki Nagaoka , Yuko Nakatake-Furuie , Kenichi Serizawa , Satoshi Kuwabara

Background

Some patients with myasthenia gravis (MG) are refractory to available treatments, highlighting the need to further understand the pathogenesis of the disease. This study aimed to determine whether components in the serum from patients with acetylcholine receptor (AChR) antibody–positive MG affect myotubes, to explore their possible role in disease pathogenesis beyond the inhibition of acetylcholine signal transmission.

Methods

Serum was collected from 14 patients with AChR antibody–positive MG. The differentiated human myotubes were stimulated with 10% serum from healthy controls or patients with MG. After 24 h, ribonucleic acid extraction/sequencing was performed, and differentially expressed genes (DEGs) were extracted. Pathway analysis was completed using DEGs that were downregulated by stimulation with serum from patients with MG. Expression of genes important for muscle contraction was measured and myotube diameter was determined by immunostaining.

Results

Approximately 1200 DEGs were extracted by comparing gene expression in cultured human myotube cells stimulated with serum from healthy controls and patients with MG. Gene ontology terms linked with muscle function were suppressed in myotube cells stimulated with patient serum. Suppression of pathways associated with muscle atrophy/weakness, decreased expression of genes associated with muscle contraction, and smaller myotube diameter were confirmed in myotube cells stimulated with serum from patients versus healthy controls.

Conclusion

Factors other than acetylcholine signal transmission inhibition may contribute to the pathogenesis of AChR antibody–positive MG. Further research is needed to clarify the pathways involved, potentially leading to more tailored pharmacotherapies.

背景：一些重症肌无力（MG）患者对现有治疗方法难治性，强调了进一步了解该疾病发病机制的必要性。本研究旨在确定乙酰胆碱受体（AChR）抗体阳性MG患者血清中的成分是否影响肌管，探讨其在抑制乙酰胆碱信号传递之外可能在疾病发病机制中的作用。方法收集14例AChR抗体阳性MG患者的血清。用10%的健康对照或MG患者血清刺激分化的人肌管。24h后进行核糖核酸提取/测序，提取差异表达基因（DEGs）。通过MG患者血清刺激下调的deg完成通路分析。测定肌肉收缩重要基因的表达，免疫染色法测定肌管直径。结果通过比较健康对照和MG患者血清刺激培养的人肌管细胞的基因表达，共提取了约1200个deg。与肌肉功能相关的基因本体术语在患者血清刺激的肌管细胞中被抑制。与健康对照相比，在患者血清刺激的肌管细胞中证实与肌肉萎缩/无力相关的通路受到抑制，与肌肉收缩相关的基因表达减少，肌管直径变小。结论AChR抗体阳性MG的发病机制可能与乙酰胆碱信号传递抑制以外的因素有关。需要进一步的研究来阐明所涉及的途径，这可能会导致更有针对性的药物治疗。

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引用次数: 0

Chronic stress, gut dysbiosis, and cholesterol metabolism: Implications for Alzheimer's disease 慢性应激、肠道失调和胆固醇代谢：对阿尔茨海默病的影响

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-06 DOI: 10.1016/j.jneuroim.2026.578853

Ashmita Das , Navya P. , Durlav Chowdhury , Arijit Das , Rahul Manna , Surendra H. Bodakhe

Alzheimer's disease is a degenerative neurological condition that gradually worsens and is the predominant type of dementia evident in millions of individuals globally. The intricate origin and development of this condition includes multiple genetic and environmental risk factors, alterations in gene expression, and activation of detrimental pathways. Chronic stress can adversely affect brain structure and function, leading to diminished cognitive ability, impaired decision-making, and poor mood regulation. The gut-brain axis, influenced by dietary and early life variables, significantly affects the control of stress responses. The human microbiota forms a symbiotic interaction with the host, impacting protective cell barriers, metabolic processes, and immune functions in the intestines. Chronic stress and high-cholesterol diets can alter gut microbiota composition, influencing behaviour, immune responses, and intestinal function. Oxysterols affect gut health and inflammation through the alteration of tight junctions and the stimulation of proinflammatory bacterial proliferation. This review provides a thorough explanation of the structure and function of the dietary stress system, its relationship with the central nervous system (CNS) and endocrine axis, and evidence connecting stress to the core processes of stress-related illnesses impacting AD. A thorough comprehension of the complex interplay among chronic stress, gut dysbiosis, and Alzheimer's disease progression could provide novel insights for the formulation of targeted therapeutic interventions.

阿尔茨海默病是一种逐渐恶化的退行性神经系统疾病，是全球数百万人的主要痴呆症类型。这种情况的复杂起源和发展包括多种遗传和环境风险因素、基因表达的改变和有害途径的激活。慢性压力会对大脑结构和功能产生负面影响，导致认知能力下降、决策能力受损、情绪调节能力差。肠脑轴受饮食和早期生活变量的影响，显著影响应激反应的控制。人类微生物群与宿主形成共生相互作用，影响肠道内的保护性细胞屏障、代谢过程和免疫功能。慢性应激和高胆固醇饮食可改变肠道菌群组成，影响行为、免疫反应和肠道功能。氧化甾醇通过改变紧密连接和刺激促炎细菌增殖来影响肠道健康和炎症。本文综述了饮食应激系统的结构和功能、与中枢神经系统（CNS）和内分泌轴的关系，以及应激与影响AD的应激相关疾病的核心过程有关的证据。全面了解慢性应激、肠道生态失调和阿尔茨海默病进展之间复杂的相互作用，可以为制定有针对性的治疗干预措施提供新的见解。

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引用次数: 0

Free light chains analysis in cerebrospinal fluid for the diagnosis of multiple sclerosis: A study in the Israeli population 脑脊液游离轻链分析诊断多发性硬化症：以色列人群的一项研究

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-25 DOI: 10.1016/j.jneuroim.2026.578873

Alina Ostrovsky, Amos J. Simon, Batia Kaplan

Background

The 2024 revision of the McDonald criteria for multiple sclerosis (MS) recognized kappa free light chain (FLCκ) as a quantitative biomarker of intrathecal immunoglobulin synthesis equivalent to oligoclonal bands (OCB). However, diagnostic performance of reported FLC thresholds vary across laboratories due to differences in instrumentation, assay type, population and regional characteristics.

Objectives

Assessing of the utility of nephelometric FLC assay for MS diagnosis in an Israeli cohort.

Methods

A total of 135 patients with MS, non-MS demyelinating/inflammatory and non-demyelinating neurological disorders were tested using FLC assay and OCB technique. FLCκ and λ concentration and their index values were estimated. Statistical analysis methods included Mann-Whitney and Kruskal-Wallis tests, Spearman correlation, and receiver operating characteristic (ROC) curves.

Results

FLCκ metrics outperformed FLCλ in diagnosing MS. Using FLCκ index, a threshold 7.0 yielded 82% specificity and 77.1% sensitivity, while 72% specificity and 82% sensitivity was achieved using κ concentration cut-off 0.19 mg/L. Specificity of OCB test (84%) was similar to that of FLCκ index, though OCB sensitivity (88.6%) exceeded the FLC-based metrics. Specifically, cases with κ index >11 and concentration > 0.2 mg/L were MS or OCB-positive, whereas cases with κ concentration < 0.1 mg/L were non-MS or OCB-negative. Hence, 60% of the cases may be safely excluded from OCB testing.

Conclusions

Optimized FLCκ thresholds effectively assist MS diagnosis within Israeli population. Combined FLC thresholds (κ index and concentration values) were established for screening clearly defined/unequivocal cases that may not require time-consuming operator-dependent OCB analysis. Rapid quantitative FLC assay holds promise as a screening tool for unequivocal cases prior to OCB testing.

2024年修订的多发性硬化症（MS）麦克唐纳标准将kappa free light chain （FLCκ）认定为鞘内免疫球蛋白合成的定量生物标志物，相当于寡克隆带（OCB）。然而，由于仪器、检测类型、人口和地区特征的差异，报告的FLC阈值的诊断性能因实验室而异。目的评价浊度FLC法在以色列人群中诊断多发性硬化症的应用价值。方法采用FLC法和OCB技术对135例多发性硬化症、非多发性硬化症脱髓鞘/炎症和非脱髓鞘神经系统疾病患者进行检测。测定FLCκ和λ浓度及其指标值。统计分析方法包括Mann-Whitney检验、Kruskal-Wallis检验、Spearman相关和受试者工作特征（ROC）曲线。结果FLCκ指标对ms的诊断优于FLCλ， FLCκ指数阈值为7.0，特异性为82%，敏感性为77.1%，而κ浓度截止值为0.19 mg/L，特异性为72%，敏感性为82%。OCB检测的特异性（84%）与FLCκ指数相似，但OCB的敏感性（88.6%）超过了基于flc的指标。其中，κ指数>；11、浓度>； 0.2 mg/L为MS或ocb阳性，κ浓度<； 0.1 mg/L为非MS或ocb阴性。因此，60%的病例可以安全地排除在OCB检测之外。结论优化后的FLCκ阈值可有效辅助以色列人群MS诊断。建立了FLC联合阈值（κ指数和浓度值），用于筛选明确定义/明确的病例，这些病例可能不需要耗时的依赖于操作者的OCB分析。快速定量FLC检测有望作为OCB检测前明确病例的筛选工具。

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引用次数: 0

Effect on disease activity of ofatumumab in the treatment of glial fibrillary acidic protein astrocytopathy and 18F-DPA714 PET/MRI imaging assessment ofatumumab治疗胶质纤维酸性蛋白星形细胞病对疾病活动性的影响及18F-DPA714 PET/MRI成像评估

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-12 DOI: 10.1016/j.jneuroim.2026.578862

Yingbo Han , Xiaoyu Chen , Qinming Zhou , Ruifen Duan , Mengmeng Zhang , Sheng Chen , Huanyu Meng

A 49-year-old male with Glial Fibrillary Acidic Protein Astrocytopathy (GFAP-A) presented with progressive cognitive decline, visual hallucinations, and bowel/bladder incontinence. Brain MRI revealed extensive white matter hyperintensities on T2-FLAIR sequences. After suboptimal response to first-line treatments including corticosteroids and intravenous immunoglobulin (IVIg), the patient was initiated on Ofatumumab (OFA) therapy. Treatment response was systematically monitored through validated clinical assessment tools (MMSE, MoCA, mRS, and CASE) and advanced neuroimaging, including conventional MRI and ¹⁸F-DPA714 PET. Following OFA treatment, the patient demonstrated marked clinical improvement and radiological resolution. Notably, ¹⁸F-DPA714 PET imaging captured dynamic changes in neuroinflammation and revealed distinct patterns not apparent on conventional MRI. This case demonstrates the potential effect on disease activity and safety of OFA in GFAP-A treatment while highlighting the value of ¹⁸F-DPA714 PET as an innovative tool for monitoring neuroinflammation and therapeutic response. To our knowledge, this represents the first comprehensive multimodal assessment using ¹⁸F-DPA714 PET/MRI in a GFAP-A patient treated with ofatumumab.

一位49岁男性胶质纤维酸性蛋白星形细胞病（gmap -A）表现为进行性认知能力下降，视觉幻觉和肠/膀胱失禁。脑MRI在T2-FLAIR序列上显示广泛的白质高信号。在对包括皮质类固醇和静脉注射免疫球蛋白（IVIg）在内的一线治疗反应不佳后，患者开始接受Ofatumumab （OFA）治疗。通过有效的临床评估工具（MMSE、MoCA、mRS和CASE）和先进的神经影像学（包括常规MRI和18F-DPA714 PET）系统监测治疗反应。经OFA治疗后，患者表现出明显的临床改善和放射学缓解。值得注意的是，18F-DPA714 PET成像捕获了神经炎症的动态变化，并显示了传统MRI上不明显的独特模式。该病例证明了OFA在gap - a治疗中对疾病活动性和安全性的潜在影响，同时强调了18F-DPA714 PET作为监测神经炎症和治疗反应的创新工具的价值。据我们所知，这是首次在接受ofatumumab治疗的gap - a患者中使用18F-DPA714 PET/MRI进行全面的多模式评估。

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引用次数: 0

B cell tolerance checkpoint function in multiple sclerosis and transient CD52 depletion B细胞耐受检查点在多发性硬化症和短暂CD52耗竭中的作用

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-05 DOI: 10.1016/j.jneuroim.2026.578854

Anastasia Alexaki , Fotis Baltoumas , Dimitrios Tzanetakos , Chrysoula Zografou , Theodoros Dame , Chrysoula Michaletou , Galini Kyriakaki , Aglaia G. Vakrakou , Maria Anagnostouli , Georgia Karadima , Marianna Tzanoudaki , Marinos C. Dalakas , Leonidas Stefanis , Konstantinos Kilidireas , Kevin C. O'Connor , Georgios Pavlopoulos , Panos Stathopoulos

Transient CD52 immune cell depletion with the monoclonal antibody alemtuzumab is highly effective in treating relapsing-remitting multiple sclerosis but often leads to secondary autoimmunity. Whether these effects are linked to an alteration of B cell tolerance mechanisms is currently not known. To evaluate peripheral B cell tolerance checkpoint integrity in patients and controls, we constructed 138 recombinant mAbs from single mature naïve B cells and tested their poly- and autoreactivity. We examined three healthy donors (HDs), three immunotherapy-naïve MS patients, and six patients treated with alemtuzumab at comparable time points post-treatment (mean ± SD 3.8 ± 0.39 years). Moreover, we investigated B cell receptor (BCR) repertoire parameters associated with tolerance mechanisms in the same subject groups. Polyreactive and autoreactive fraction means did not differ significantly among the three subgroups. Presence of a high or low autoreactive fraction of naïve B cells in patients treated with alemtuzumab did not correlate with secondary autoimmunity at the time of sampling and with future MS activity, and therefore most likely reflects stochastic variation in the context of immune reconstitution. In BCR repertoire analysis, alemtuzumab-treated patients showed lower mean naïve complementarity-determining region 3 (CDR3) net charge compared to HDs (P = 0.0036), an interesting yet isolated finding warranting further investigation. Overall, transient CD52 depletion did not seem to affect major changes in peripheral B cell tolerance checkpoint function as assessed with naïve B cell cloning and BCR NGS, while observations in the described setting may also apply to other immune reconstitution therapies.

短暂的CD52免疫细胞耗竭与单克隆抗体阿仑妥珠单抗在治疗复发-缓解型多发性硬化方面非常有效，但经常导致继发性自身免疫。这些影响是否与B细胞耐受机制的改变有关目前尚不清楚。为了评估患者和对照组外周B细胞耐受检查点的完整性，我们从单个成熟naïve B细胞中构建了138个重组单克隆抗体，并测试了它们的多反应性和自身反应性。我们在治疗后的可比较时间点（平均±SD 3.8±0.39年）检查了3名健康供体（hd）、3名immunotherapy-naïve MS患者和6名接受阿仑单抗治疗的患者。此外，我们还研究了相同受试者组中与耐受机制相关的B细胞受体（BCR）库参数。多反应性和自反应性分数均值在三个亚组之间无显著差异。在接受阿仑单抗治疗的患者中，naïve B细胞的高或低自身反应部分与采样时的继发性自身免疫和未来的MS活性无关，因此很可能反映了免疫重建背景下的随机变异。在BCR全库分析中，与hd相比，阿仑单抗治疗的患者表现出更低的naïve互补决定区3 （CDR3）平均净电荷（P = 0.0036），这是一个有趣但孤立的发现，值得进一步研究。总体而言，通过naïve B细胞克隆和BCR NGS评估，短暂的CD52耗尽似乎不会影响外周B细胞耐受检查点功能的主要变化，而上述情况的观察结果也可能适用于其他免疫重建疗法。

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引用次数: 0

The NEDD8-activating enzyme inhibitor MLN4924 reduces inflammation, blood-brain barrier disruption and brain injury after intracerebral hemorrhage in mice nedd8活化酶抑制剂MLN4924可减轻小鼠脑出血后的炎症、血脑屏障破坏和脑损伤

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-26 DOI: 10.1016/j.jneuroim.2026.578872

Yu Huang , Zihan Wang , Shaochen Wang , Chenxi Liu , Luping Chang , Xue Geng , Pengyue Du , Yong-Chen Wang , Wenying Fan , Bing-Qiao Zhao

Inflammation is a key factor leading to secondary brain injury after intracerebral hemorrhage (ICH). Neddylation, a post-translational modification that attaches NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8) to targets, regulates diverse cellular processes. Neddylation is overactivated in various cancers and linked to atherosclerosis and inflammatory disorders, but its role in ICH remains unclear. In this study, mice were subjected to ICH by injection of collagenase. The NEDD8-activating enzyme inhibitor MLN4924 was administered subcutaneously post-ICH. We found that NEDD8 expression was upregulated in macrophages and microglia after ICH. Treatment with MLN4924 reduced NEDD8 expression, cullin-1 neddylation, macrophage infiltration, microglial activation, and the production of proinflammatory cytokines. These anti-inflammatory effects were accompanied by attenuated loss of tight junction proteins, blood-brain barrier (BBB) damage, neuronal degeneration and brain injury, and improved neurological function. Furthermore, MLN4924 treatment induced the accumulation of the cullin-RING E3 ligase substrates, including phosphorylated ERK5 and KLF2, and reduced ICAM-1 expression. Inhibiting ERK5 reversed the beneficial effects of MLN4924 on inflammation, BBB disruption, and neurobehavioral deficits. Collectively, inhibition of the NEDD8 pathway by MLN4924 attenuates inflammation, BBB disruption, and neurological deficits via the p-ERK5-KLF2-ICAM-1 axis, highlighting NEDD8 pathway as a potential therapeutic target for ICH.

炎症是导致脑出血后继发性脑损伤的关键因素。类化修饰是一种翻译后修饰，将NEDD8（神经元前体细胞表达的发育下调蛋白8）连接到靶标上，调节多种细胞过程。类化修饰在多种癌症中过度激活，并与动脉粥样硬化和炎症性疾病有关，但其在脑出血中的作用尚不清楚。在本研究中，小鼠通过注射胶原酶致脑出血。脑出血后皮下注射nedd8活化酶抑制剂MLN4924。我们发现脑出血后巨噬细胞和小胶质细胞中NEDD8的表达上调。用MLN4924治疗可降低NEDD8表达、cullin-1类泛素化、巨噬细胞浸润、小胶质细胞活化和促炎细胞因子的产生。这些抗炎作用伴随着紧密连接蛋白的减少、血脑屏障（BBB）损伤、神经元变性和脑损伤，以及神经功能的改善。此外，MLN4924处理诱导cullin-RING E3连接酶底物的积累，包括磷酸化的ERK5和KLF2，并降低ICAM-1的表达。抑制ERK5逆转了MLN4924对炎症、血脑屏障破坏和神经行为缺陷的有益作用。总的来说，MLN4924抑制NEDD8通路可通过p-ERK5-KLF2-ICAM-1轴减轻炎症、血脑屏障破坏和神经功能缺陷，突出NEDD8通路是脑出血的潜在治疗靶点。

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引用次数: 0

Exosomes derived from neural stem cells contribute to cerebral ischemia/reperfusion injury via inhibiting autophagy in rats 神经干细胞来源的外泌体通过抑制自噬参与大鼠脑缺血再灌注损伤

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-29 DOI: 10.1016/j.jneuroim.2026.578875

Li Xiong , Siying Huo , Yuan Yang , Qi Zhang , Junjie Li , Wenya Bai , Jia Liu , Jianlin Shao

Background

Cerebral ischemia-reperfusion injury (CIRI) represents a critical pathological mechanism underlying stroke. Exosomes (EXOs) are biological vesicles released by cells, containing active components and functional properties of their cell of origin. This study investigates the impact of human neural stem cell-derived exosomes (hNSC-EXOs) on the CIRI rat model, focusing on neuronal autophagy, and provides a novel theoretical foundation for future clinical interventions in CIRI management.

Methods

PKH26-labeled hNSC-EXOs were traced in vivo and in vitro. After establishing CIRI model, hNSC-EXOs were administered for treatment. Brain injury and variations in inflammatory factors were compared at 24 h after operation. The impact of hNSC-EXOs on neuronal autophagy was examined by detecting the expression of Beclin-1, Atg-5, and LC3B, and observing the changes in the number of autophagosomes using TEM of the right cerebral cortex of rats.

Results

The average particle size and concentration of hNSC-EXO were 64.47 nm and 8.96 × 10¹⁰/ml, respectively. PKH26-labeled hNSC-EXOs was taken up by BV2 and HT22 cells, and was mainly located in the brain injury area in vivo, with their total flux showing a time-dependent characteristic. hNSC-EXO treatment reduced the neurological score, cerebral infarct volume, and cerebral edema in the CIRI model. Brain tissue staining showed that hNSC-EXO attenuated Nissl body damage and neuronal apoptosis in the CIRI model. Regarding inflammatory factors, hNSC-EXO increased serum levels of IL-4 and IL-10, and decreased levels of TNF-α, iNOS, and IL-6 in the CIRI model. Notably, hNSC-EXO reduced the expression of Beclin-1, Atg-5, and LC3 and the number of autophagosomes in the brain tissue of the CIRI model.

Conclusion

hNSC-EXOs exert an antagonistic effect with CIRI, effectively inhibiting excessive neuronal autophagy, reducing the inflammatory response and neuronal apoptosis.

脑缺血再灌注损伤（CIRI）是脑卒中的一个重要病理机制。外泌体（exosome, EXOs）是细胞释放的生物囊泡，含有原细胞的活性成分和功能特性。本研究探讨了人类神经干细胞衍生外泌体（hNSC-EXOs）对CIRI大鼠模型的影响，重点关注神经元自噬，为未来临床干预CIRI管理提供新的理论基础。方法在体内和体外对spkh26标记的hnsc - exo进行追踪。建立CIRI模型后，给予hnsc - exo治疗。术后24 h比较脑损伤及炎症因子变化。通过大鼠右脑皮层透射电镜检测Beclin-1、Atg-5、LC3B的表达，观察自噬体数量的变化，探讨hNSC-EXOs对神经元自噬的影响。结果hNSC-EXO的平均粒径为64.47 nm，平均浓度为8.96 × 1010/ml。pkh26标记的hNSC-EXOs被BV2和HT22细胞摄取，在体内主要分布于脑损伤区，其总通量呈时间依赖性。hNSC-EXO治疗降低了CIRI模型的神经学评分、脑梗死体积和脑水肿。脑组织染色显示，hNSC-EXO可减轻CIRI模型的Nissl体损伤和神经元凋亡。在炎症因子方面，hNSC-EXO增加了CIRI模型中血清IL-4和IL-10水平，降低了TNF-α、iNOS和IL-6水平。值得注意的是，hNSC-EXO降低了CIRI模型脑组织中Beclin-1、Atg-5和LC3的表达以及自噬体的数量。结论hnsc - exos对CIRI具有拮抗作用，可有效抑制神经元过度自噬，减少炎症反应和神经元凋亡。

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引用次数: 0

TMEM132A autoimmunity in patients with suspected autoimmune cerebellar ataxia 怀疑自身免疫性小脑性共济失调患者的TMEM132A自身免疫

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-04-01 Epub Date: 2026-01-14 DOI: 10.1016/j.jneuroim.2026.578867

Akio Kimura , Akira Takekoshi , Yuri Miyazaki , Kentaro Oh-hashi , Sachiko Kamada , Yukie Taguchi , Masashiro Sugawara , Tsubasa Watanabe , Yuji Ueno , Hiroaki Yaguchi , Ichiro Yabe , Yuko Fukata , Masaki Fukata , Takayoshi Shimohata

Autoimmune cerebellar ataxia (ACA) refers to immune-mediated cerebellar ataxia. The autoantibodies involved in ACA can be detected in patients and are important biomarkers. In this study, we aimed to identify a novel autoantibody in patients with ACA. We screened for autoantibodies in serum samples from patients with cerebellar ataxia using immunohistochemical and immunocytochemical assays. Immunoprecipitation and mass spectrometry were used to identify the target antigens of the detected autoantibodies. We found that IgG reacted with transmembrane protein family 132 A (TMEM132A), which is enriched in the central nervous system (CNS), in serum samples of patients with cerebellar ataxia. A cell-based binding assay (CBA) was used to identify TMEM132A-IgG in serum samples obtained from 436 patients with cerebellar ataxia requiring differential diagnosis for ACA, 62 patients with autoimmune encephalitis, 27 patients with multiple system atrophy with predominant cerebellar ataxia, 24 patients with multiple sclerosis, 17 patients with neuromyelitis optica spectrum disorders, 17 patients with Parkinson's disease, 7 patients with anti-myelin oligodendrocyte glycoprotein antibody-associated disease, and 14 healthy subjects. We detected TMEM132A-IgG in serum samples from two patients with cerebellar ataxia, including the patient whose study first led to the identification of this autoantibody. None of the other participants had these autoantibodies. The two autoantibody-positive patients showed progressive predominant cerebellar ataxia with pyramidal tract signs and albuminocytologic dissociation. Brain MRI findings indicated cerebellar atrophy in one patient and bilateral inferior olivary nuclei hyperintensity changes and pseudohypertrophy in the other patient. TMEM132 A-IgG may be a novel autoantibody associated with autoimmune CNS diseases, including ACA.

自身免疫性小脑共济失调（ACA）是指免疫介导的小脑共济失调。ACA相关的自身抗体可以在患者体内检测到，是重要的生物标志物。在这项研究中，我们的目的是在ACA患者中鉴定一种新的自身抗体。我们使用免疫组织化学和免疫细胞化学方法筛选小脑性共济失调患者血清样本中的自身抗体。采用免疫沉淀法和质谱法对检测到的自身抗体的靶抗原进行鉴定。在小脑性共济失调患者的血清样本中，我们发现IgG与富集于中枢神经系统的跨膜蛋白家族132A （TMEM132A）发生反应。采用细胞结合法（CBA）对436例需要鉴别诊断ACA的小脑性共济失调患者、62例自身免疫性脑炎患者、27例多系统萎缩伴特发性小脑性共济失调患者、24例多发性硬化症患者、17例视神经脊髓炎患者、17例帕金森病患者的血清样本进行TMEM132A-IgG的鉴定。抗髓鞘少突胶质细胞糖蛋白抗体相关疾病7例，健康对照14例。我们在两名小脑性共济失调患者的血清样本中检测到TMEM132A-IgG，其中包括在研究中首次鉴定出这种自身抗体的患者。其他参与者都没有这些自身抗体。两例自身抗体阳性患者表现为进行性占优势的小脑性共济失调，伴有锥体束征象和白蛋白细胞分离。脑MRI显示一名患者小脑萎缩，另一名患者双侧下橄榄核高强度改变和假性肥大。TMEM132 a - igg可能是一种与自身免疫性中枢神经系统疾病（包括ACA）相关的新型自身抗体。

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引用次数: 0

TNF-α in schizophrenia: Associations with cholesterol and genetic variations. 精神分裂症中的TNF-α：与胆固醇和遗传变异有关。

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology

Pub Date : 2026-03-18 DOI: 10.1016/j.jneuroim.2026.578910

Xue Xin Goh, Pek Yee Tang, Kok Yoon Chee, Shiau Foon Tee

Tumor necrosis factor-α (TNF-α), a pro-inflammatory factor is involved in the pathophysiology of schizophrenia. The roles of antipsychotics, cholesterol, and TNFA single nucleotide polymorphisms (SNPs) on elevation of TNF-α in schizophrenia have been inadequately evaluated. Therefore, the present study aimed to compare serum TNF-α level between Malaysian patients with schizophrenia and healthy controls, as well as to investigate the effects of antipsychotics, cholesterol, and TNFA SNPs (rs361525, rs1800629, and rs1800630) on serum TNF-α level in schizophrenia. This study involved 150 medicated outpatients with schizophrenia and 139 healthy controls. Their blood was collected and processed into serum. Serum TNF-α, high-density lipoprotein cholesterol (HDLC), and low-density lipoprotein cholesterol (LDL-C) levels were measured. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to genotype TNFA SNPs. After covariate adjustment, our findings demonstrated significantly increased serum TNF-α and HDL-C levels in patients, and there was a significant association between serum LDL-C and TNF-α levels in this group. Meanwhile, there was no significant association between antipsychotics and serum TNF-α levels. This could be due to the overlapping pro- or anti-inflammatory effects of each antipsychotic as some of the patients were not on monotherapy. However, TNFA rs361525 polymorphism significantly modified the association between schizophrenia and serum TNF-α level. In conclusion, this study suggested that the elevated level of TNF-α in schizophrenia may be influenced by cholesterol and TNFA polymorphisms.

肿瘤坏死因子-α (TNF-α)是一种促炎因子，参与了精神分裂症的病理生理过程。抗精神病药物、胆固醇和TNFA单核苷酸多态性（snp）对精神分裂症患者TNF-α升高的作用尚未得到充分评估。因此，本研究旨在比较马来西亚精神分裂症患者与健康对照者血清TNF-α水平，并探讨抗精神病药物、胆固醇和TNFA snp （rs361525、rs1800629和rs1800630）对精神分裂症患者血清TNF-α水平的影响。这项研究涉及150名接受药物治疗的精神分裂症门诊患者和139名健康对照。他们的血液被收集并加工成血清。测定血清TNF-α、高密度脂蛋白胆固醇（HDLC）、低密度脂蛋白胆固醇（LDL-C）水平。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对TNFA snp进行基因分型。在协变量调整后，我们的研究结果显示患者血清TNF-α和HDL-C水平显著升高，并且该组血清LDL-C和TNF-α水平之间存在显著关联。同时，抗精神病药物与血清TNF-α水平无显著相关性。这可能是由于每种抗精神病药物的促炎或抗炎作用重叠，因为一些患者没有接受单一治疗。然而，TNFA rs361525多态性显著改变了精神分裂症与血清TNF-α水平之间的关系。综上所述，本研究提示精神分裂症患者TNF-α水平升高可能受胆固醇和TNF-α多态性的影响。

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引用次数: 0