Lénia Silva , Isabel Fonseca Silva , Tomás Fonseca , Luísa Serpa Pinto , Bárbara Leal , Paulo Pinho e Costa , Liliana Igreja , Bruno Moreira , Ernestina Santos , Carlos Vasconcelos , António Marinho , João Araújo Correia
{"title":"A 30-year experience in neuro-Behçet disease","authors":"Lénia Silva , Isabel Fonseca Silva , Tomás Fonseca , Luísa Serpa Pinto , Bárbara Leal , Paulo Pinho e Costa , Liliana Igreja , Bruno Moreira , Ernestina Santos , Carlos Vasconcelos , António Marinho , João Araújo Correia","doi":"10.1016/j.jneuroim.2025.578647","DOIUrl":"10.1016/j.jneuroim.2025.578647","url":null,"abstract":"<div><h3>Background</h3><div>Behçet disease (BD) is a systemic vasculitis affecting multiple organs with a wide range of severity. Neuro-Behçet (NBD) is a severe form, characterized by high morbidity, disability, and mortality rates.</div></div><div><h3>Methods</h3><div>Retrospective analysis (1993–2023) of neurological involvement in BD patients at a tertiary center.</div></div><div><h3>Results</h3><div>Of 296 BD patients, 93(31.4 %) underwent neurological evaluation. Definite NBD was identified in 30(10.1 %), probable NBD in 2(0.5 %) and “other neurological symptoms in BD” in 26(8.6 %) patients. The definite NBD group (median age: 36 years, 50 % female) had 44 neurological attacks: 24(55 %) parenchymatous and 20(45 %) non-parenchymatous. The most common syndromes were brainstem (27.3 %) and multifocal (25.6 %), with ataxia being the most frequent sign (40.9 %). One-third had a relapsing course. NBD onset concurred with BD diagnosis in 50 % of cases, followed in 30 %, and preceded in 20 %. Brain MRI revealed predominant involvement of the brainstem and diencephalic regions. The HLA-B*51 allele was more prevalent in definite NBD versus BD patients (53.8 % vs 31.2 %, <em>p</em> = 0.036). Treatments included corticosteroids (70.5 %), cyclophosphamide (15.9 %), infliximab (9.1 %), and conventional synthetic disease-modifying antirheumatic drugs (13.6 %). Better outcomes were achieved with cyclophosphamide and infliximab. The probable NBD and “other neurological symptoms in BD” groups (median age: 37 years) were mostly female (92.9 %). Headache (85 %) and cognitive complaints (23 %) were common symptoms.</div></div><div><h3>Conclusions</h3><div>Distinguishing features were the absence of sex predominance and the NBD frequency preceding BD diagnosis. HLA-B*51 is an apparent risk factor for definite NBD. Anti-TNFα biological therapy has proven effective in NBD. Neurological involvement in BD aligned with existing literature.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"406 ","pages":"Article 578647"},"PeriodicalIF":2.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johannes Weigel, Luise Appeltshauser, Claudia Sommer, Kathrin Doppler
{"title":"Proprioceptive endings at muscle spindles as a possible target of autoantibodies","authors":"Johannes Weigel, Luise Appeltshauser, Claudia Sommer, Kathrin Doppler","doi":"10.1016/j.jneuroim.2025.578648","DOIUrl":"10.1016/j.jneuroim.2025.578648","url":null,"abstract":"<div><div>Autoimmune nodopathies are characterized by autoantibodies targeting proteins of the nodes of Ranvier of peripheral nerves. Anti-Contactin-1 (CNTN1) autoantibodies are associated with sensorimotor neuropathy and severe sensory ataxia. While damage to the nodal architecture due to axoglial disjunction is considered the primary pathogenic mechanism of autoimmune nodopathies, the reason for the severe sensory ataxia, accompanied by proprioceptive impairment, remains unclear. We therefore aimed to investigate the expression of CNTN1 in muscle spindles and the binding of IgG from patients with anti-CNTN1 and other paranodal/nodal autoantibodies to these structures.</div><div>Using immunofluorescence staining of murine muscle tissue, we demonstrate that CNTN1 is expressed in annulospiral fibers of muscle spindles. IgG from patients with anti-CNTN1 autoantibodies showed specific binding to these structures, whereas IgG of patients with other paranodal autoantibodies did not. Additionally, IgG from a subset of patients with autoimmune neuropathy and severe sensory ataxia that were negatively tested for paranodal autoantibodies showed distinct binding to annulospiral fibers.</div><div>Our findings suggest that CNTN1 might play a role in proprioceptive signal transmission at annulospiral fibers and autoantibody-mediated dysfunction at annulospiral fibers may contribute to severe sensory ataxia. These results highlight annulospiral fibers as potential targets for future research on autoantibody-mediated neuropathies.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578648"},"PeriodicalIF":2.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reflections on the influence of seasonal and environmental factors in myasthenia gravis","authors":"Zi Yin Yao","doi":"10.1016/j.jneuroim.2025.578645","DOIUrl":"10.1016/j.jneuroim.2025.578645","url":null,"abstract":"","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578645"},"PeriodicalIF":2.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Anti–IL-6R antibody treatment changes microglial phenotype in AQP4 peptide–immunized mice, leading to suppression of myelitis severity","authors":"Shota Miyake , Yoshichika Katsura , Masayuki Baba, Haruna Tomizawa-Shinohara, Yoshihiro Matsumoto, Kenichi Serizawa","doi":"10.1016/j.jneuroim.2025.578644","DOIUrl":"10.1016/j.jneuroim.2025.578644","url":null,"abstract":"<div><div>Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by periods of remission and relapse; severe relapses often lead to permanent neurological disability. Satralizumab, an anti–interleukin-6 receptor (anti–IL-6R) antibody, has been proven in previous studies to reduce the frequency and severity of relapses in patients with NMOSD. There are several reports on the mechanisms through which anti–IL-6R antibodies are thought to suppress relapse. However, the mechanisms underlying how anti–IL-6R antibodies reduce the severity of myelitis have not been elucidated. We investigated the effect of an anti–IL-6R antibody (MR16–1) on the severity of myelitis in an AQP4 peptide–immunized mice model. This mouse model exhibits NMOSD-like pathological characteristics and the production of anti-AQP4 autoantibodies. Unlike the previously reported experimental protocol where antibody and peptide are administered simultaneously, we tested delayed administration of MR16–1 (9 days after peptide immunization). We found that delayed MR16–1 administration suppressed the clinical score of AQP4 peptide–immunized mice experiencing myelitis. Mice treated with MR16–1 showed a greater percentage of CD11c<sup>+</sup> microglia in the spinal cord, along with upregulated expression of phagocytosis-related genes. Blockade of IL-6R by anti–IL-6R antibodies may suppress the severity of myelitis by increasing CD11c<sup>+</sup> microglia and enhancing phagocytic function in AQP4 peptide–immunized mice.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578644"},"PeriodicalIF":2.9,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hong Zheng , Zhang-Yang Xu , Ting Hu , Yi-Lin Wu , Chen-Wei Huang , Jia-Mei Li , Zhi-Yong Cao , Wei Wang , Chun-Lei Jiang , Wen-Jun Su
{"title":"RIPK3-MLKL dependent necroptosis mediates depressive-like behavior by facilitating neuroinflammation","authors":"Hong Zheng , Zhang-Yang Xu , Ting Hu , Yi-Lin Wu , Chen-Wei Huang , Jia-Mei Li , Zhi-Yong Cao , Wei Wang , Chun-Lei Jiang , Wen-Jun Su","doi":"10.1016/j.jneuroim.2025.578643","DOIUrl":"10.1016/j.jneuroim.2025.578643","url":null,"abstract":"<div><h3>Background</h3><div>Neuroinflammation is a critical pathophysiological mechanism of depression. But the sources and processes involved remain unclear. Recent reports suggest that necroptosis with pro-inflammatory properties may facilitate inflammation. Therefore, we investigated the potential role of necroptosis-associated neuroinflammation in depression.</div></div><div><h3>Methods</h3><div>Depression model mice induced by intraperitoneal injection of lipopolysaccharide (LPS) were treated with RIPK1 inhibitor Necrostatin-1 s (Nec-1 s, 6 mg/kg), RIPK3 inhibitor GSK′872 (6 mg/kg) or intracerebroventricular injection of MLKL inhibitor GW806742X (5 μL of 200 μmol/L). Depressive-like behaviors were assessed using sucrose preference test and tail suspension test. Serum inflammatory cytokines were detected by ELISA, while glial biomarkers were determined by western blots. Hematoxylin & eosin and immunohistochemical staining were utilized to identify morphological characteristics of necroptotic cells in the hippocampus and prefrontal cortex. Further, specific molecules involved in necroptotic pathway were measured by immunoblots.</div></div><div><h3>Results</h3><div>Mice treated with LPS exhibited depressive-like behaviors, as well as increased inflammatory cytokines, enhanced MLKL phosphorylation, and decreased cleaved Caspase-8 levels in hippocampus. GSK′872 rather than Nec-1 s exhibited significant antidepressant effects. Although necroptosis was present in both the hippocampus and prefrontal cortex, neuroinflammation was mainly manifested in the hippocampus. Additionally, GSK′872 restored the elevated levels of IL-1β, TNF-α, and HMGB1 in the serum and hippocampus of model mice, and simultaneously ameliorated necroptosis. However, neither GSK’872 nor Nec-1 s had sufficient effect on Caspase-8 and microgliosis. Furthermore, intracerebroventricular injection of GW806742X improved depressive-like behavior and neuroinflammation in hippocampus.</div></div><div><h3>Conclusion</h3><div>This study provides novel evidence that hippocampal RIPK3-MLKL-dependent necroptosis mediates depressive-like behavior induced by inflammatory stress. During this process, necroptosis may facilitate neuroinflammation by promoting the release of HMGB1. Interventions targeting this pathway may help treat depression with an inflammatory phenotype.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578643"},"PeriodicalIF":2.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Knockdown of YTHDF2 mitigates OGD-induced microglial inflammation by preventing m6A-dependent PARP14 degradation","authors":"Bin Li, Ruixi Ming","doi":"10.1016/j.jneuroim.2025.578636","DOIUrl":"10.1016/j.jneuroim.2025.578636","url":null,"abstract":"<div><div>Neuroinflammation is a key pathological factor in ischemic brain diseases, contributing to the initiation and progression of these conditions. The function of the m<sup>6</sup>A reader protein YTHDF2 in regulating neuroinflammation across various neurological contexts. To elucidate the role and regulatory mechanism of YTHDF2 in inflammation under ischemic-like conditions, this study employed an in vitro model, exposing microglia to oxygen-glucose deprivation (OGD) to mimic the stress environment. And through YTHDF2 knockdown, we investigated its effect on OGD-induced inflammation. The results demonstrated that YTHDF2 knockdown significantly suppressed the expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), in OGD-treated microglia. Mechanistic analysis revealed that YTHDF2 interacts with <em>Parp14</em> mRNA under OGD conditions, reducing its RNA stability via m<sup>6</sup>A-dependent mechanisms, which in turn decreases Poly (ADP-ribose) polymerase family, member 14 (PARP14) protein expression. Additionally, YTHDF2 knockdown after OGD promoted a PARP14-driven phenotypic switch in microglia from the pro-inflammatory M1 state to the anti-inflammatory M2 state, resulting in diminished inflammation. These findings offer new insights into the regulatory function of YTHDF2 in OGD-induced microglial inflammation and propose m<sup>6</sup>A modification as a potential therapeutic target for alleviating neuroinflammation.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578636"},"PeriodicalIF":2.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Anti-IL-6 receptor antibody suppresses onset of paralytic symptoms in AQP4 peptide-immunized mice without lowering bone strength or mineral density","authors":"Haruna Tomizawa-Shinohara, Yoshihiro Matsumoto, Shota Miyake, Yoshichika Katsura, Keisuke Tanaka, Kenichi Serizawa","doi":"10.1016/j.jneuroim.2025.578635","DOIUrl":"10.1016/j.jneuroim.2025.578635","url":null,"abstract":"<div><div>Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by the production of autoantibodies against aquaporin-4 (AQP4). Treatment with prednisolone (PSL) or anti-IL-6 receptor (IL-6R) antibody can reduce the frequency of relapse in patients with AQP4 antibody-positive NMOSD. We previously established a mouse model of paralysis induced by intradermal immunization with AQP4 peptide. In this study, we investigated the effects of PSL and anti-IL-6R antibody treatment on paralysis and on bone fragility in this NMOSD mouse model. Prednisolone and anti-IL-6R antibody treatment each suppressed the clinical scores and incidence of paralytic symptoms in AQP4 peptide-immunized mice. High-PSL treatment induced thinning of cortical bone and reduction of tissue mineral density in the femoral shaft and a decrease in femoral bone strength, although it increased bone volume/tissue volume in the trabecular bone of the distal femur. In contrast, anti-IL-6R treatment showed no significant differences in bone strength or cortical thickness compared to the non-immunized naive group. Bone morphometric analysis showed that high-PSL treatment reduced the bone formation rate in both cortical and trabecular bone, with a predominance of bone resorption, whereas anti-IL-6R treatment demonstrated no notable effect on bone metabolism. These results suggest that anti-IL-6R antibody can prevent the development of paralytic symptoms in AQP4 peptide-immunized mice without reducing bone strength.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578635"},"PeriodicalIF":2.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Veronica Viola , Gian Maria Asioli , Lorenzo Ferri , Simone Rossi , Elisa Andrini , Elisabetta Pierucci , Giuseppe Lamberti , Luisa Sambati , Rita Rinaldi , Francesca Bisulli , Luca Spinardi , Maria Guarino
{"title":"Multifocal paraneoplastic encephalitis associated with anti-GABA-B and anti-Hu antibodies manifesting with status epilepticus and epilepsia partialis continua: Expanding the clinical-radiological spectrum","authors":"Veronica Viola , Gian Maria Asioli , Lorenzo Ferri , Simone Rossi , Elisa Andrini , Elisabetta Pierucci , Giuseppe Lamberti , Luisa Sambati , Rita Rinaldi , Francesca Bisulli , Luca Spinardi , Maria Guarino","doi":"10.1016/j.jneuroim.2025.578634","DOIUrl":"10.1016/j.jneuroim.2025.578634","url":null,"abstract":"<div><div>Paraneoplastic neurological syndromes (PNSs) are immune-mediated effects of remote cancer, which often harbor anti-neuronal antibodies. These antibodies may direct toward intracellular or cell-surface antigens and the clinical picture associated with each antibody is often stereotyped. Little is known about clinical and radiological manifestations of PNSs with co-occurring anti-intracellular and anti-surface neuronal antigens. This case report describes a unique case of a patient with small cell lung cancer harboring both anti-GABABR and anti-Hu antibodies who presented with multifocal encephalitis, manifesting with status epilepticus and epilepsia partialis continua.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578634"},"PeriodicalIF":2.9,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification of shared pathophysiological molecules of major psychiatric disorders: A comprehensive analysis of serum immune complex antigens before and after electroconvulsive therapy","authors":"Yuki Jimbayashi Kutsuna , Nozomi Aibara , Junya Hashizume , Wataru Omori , Mami Okada-Tsuchioka , Naoto Kajitani , Mikiro Nakashima , Atsushi Kawakami , Kaname Ohyama , Minoru Takebayashi","doi":"10.1016/j.jneuroim.2025.578623","DOIUrl":"10.1016/j.jneuroim.2025.578623","url":null,"abstract":"<div><div>Recent studies indicate common inflammatory findings have been identified in peripheral blood in patients with major psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Electroconvulsive therapy (ECT) frequently improves both severe symptoms and inflammatory markers in these conditions. However, the shared inflammatory mechanisms underlying these disorders, and thus, reliable biomarkers remain unclear. We hypothesized that the activation of immune complexes (ICs) contributes to inflammatory pathogenesis of these disorders. Using immune complexome analysis, we examined antigens forming ICs (IC-antigens) in the serum of patients with SCZ, BD, and MDD (<em>n</em> = 60) before and after ECT. Our analysis showed that although the overall quantity of ICs did not change before and after ECT, four proteins significantly decreased following ECT. These proteins were DENN domain-containing protein 1C (DENND1C), double-stranded RNA-specific editase 1 (ADARB1), perilipin-4, and coagulation factor XI, which were all consistently detected as IC-antigens across patient groups. Notably, DENND1C, ADARB1, and perilipin-4 were specific to psychiatric patients and absent in healthy controls. The abundance of these IC-antigens significantly correlated with psychiatric symptom scores, with DENND1C showing a particularly strong correlation with total symptom scores across all three disorders. These findings suggest that DENND1C may contribute to the shared pathophysiology of SCZ, BD, and MDD through antigenization or IC formation. This highlights its potential as a biomarker for ECT treatment availability and diagnostic/treatment efficacy monitoring.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"405 ","pages":"Article 578623"},"PeriodicalIF":2.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}