Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"<i>Neurology® Neuroimmunology and Neuroinflammation</i> Enters Its Second Decade.","authors":"Scott S Zamvil","doi":"10.1212/NXI.0000000000200385","DOIUrl":"10.1212/NXI.0000000000200385","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200385"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescein Angiography as a Surrogate Marker of Disease Activity in Susac Syndrome.","authors":"Laura Guttieres, Lea Vannelli, Sarah Demortiere, Marine Perriguey, Maya Elziere, Pierre Durozard, Clemence Boutiere, Audrey Rico, Frederic Hilezian, Jan-Patrick Stellmann, Jean Pelletier, Adil Maarouf, Natacha Stolowy, Bertrand Audoin","doi":"10.1212/NXI.0000000000200379","DOIUrl":"10.1212/NXI.0000000000200379","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate the sensitivity of fluorescein angiography (FA) in detecting disease activity in Susac syndrome.</p><p><strong>Methods: </strong>We conducted a blinded analysis of all FA, brain MRI, and audiogram examinations performed throughout the follow-up of patients with Susac syndrome.</p><p><strong>Results: </strong>A total of 79 FA examinations, 85 brain MRI scans, and 49 audiograms were analyzed from 9 patients followed for a mean (SD) period of 6 (4) years. Disease activity was detected in 41.5% of FA examinations, 10.5% of MRI scans, and 25% of audiograms (FA vs MRI, <i>p</i> < 0.0001; FA vs audiogram, <i>p</i> = 0.06; audiogram vs MRI, <i>p</i> < 0.05). Within 3 months of clinical relapses, activity was observed in 57%, 24%, and 27% of FA, MRI, and audiogram examinations, respectively (FA vs MRI, <i>p</i> < 0.05; FA vs audiogram, <i>p</i> = 0.09; audiogram vs MRI, <i>p</i> = 1). Quantitative analysis of FA showed a mean (SD) of 2.5 (2.5) leakages (both eyes) during relapses compared with 1.2 (1.4) during remission (<i>p</i> < 0.05).</p><p><strong>Discussion: </strong>FA, particularly arterial leakage, demonstrated the highest sensitivity in detecting disease activity and may be a valuable tool for treatment management in Susac syndrome. Future studies with larger samples should aim to identify the optimal threshold of FA changes associated with an increased risk of relapse.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200379"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies: A Case Report.","authors":"Marjolijn S W Quaak, Michiel S J Buijze, Virginie J M Verhoeven, Clementien Vermont, Emilie P Buddingh, Maud Heredia, Janneke N Samsom, Maarten J Titulaer, Annemarie M C van Rossum, Sylvia Kamphuis, Rinze Frederik Neuteboom","doi":"10.1212/NXI.0000000000200381","DOIUrl":"10.1212/NXI.0000000000200381","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200381"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progressive Myelitis in a 63-Year-Old Woman: A Case Report From the National Multiple Sclerosis Society Case Conference Proceedings.","authors":"Kimberly A DiMauro, Morgan E Heber, Jonathan Lee, Jeffrey A Cohen, Eoin P Flanagan, Claire Riley, Myla D Goldman, Scott S Zamvil, Amy C Kunchok","doi":"10.1212/NXI.0000000000200382","DOIUrl":"10.1212/NXI.0000000000200382","url":null,"abstract":"<p><p>We present a case of myelitis in a 63-year-old woman with breast adenocarcinoma treated with pembrolizumab. MRI showed multiple T2-hyperintense lesions throughout the spinal cord, and CSF demonstrated lymphocytic pleocytosis. We discuss the differential diagnosis of myelitis in the setting of cancer and immune checkpoint inhibitors.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200382"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired Presynaptic Function Contributes Significantly to the Pathology of Glycine Receptor Autoantibodies.","authors":"Anna-Lena Wiessler, Fang Zheng, Christian Werner, Margarita Habib, Erdem Tuzun, Christian Alzheimer, Claudia Sommer, Carmen Villmann","doi":"10.1212/NXI.0000000000200364","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200364","url":null,"abstract":"<p><strong>Background and objectives: </strong>Autoantibodies (aAbs) against glycine receptors (GlyRs) are mainly associated with the rare neurologic diseases stiff person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM). GlyR aAbs are also found in other neurologic diseases such as epilepsy. The aAbs bind to different GlyR α-subunits and, more rarely, also to the GlyR β-subunit. So far, studies on the pathogenic effects of the aAbs have focused on postsynaptic, heteromeric GlyRs, reporting a loss of ion channel function and receptor internalization upon aAb binding. We asked whether the aAbs also affect expression and functionality of presynaptic homomeric GlyRs.</p><p><strong>Methods: </strong>We established interneuron cultures from mouse embryonic spinal cord neurons and used protein biochemistry and super-resolution microscopy to determine aAb binding to presynaptic GlyRs in a uniform neuronal subpopulation. Brainstem slice recordings were used to detect functional alterations.</p><p><strong>Results: </strong>Several days-long exposure of spinal cord cultures with GlyR aAbs did not change expression levels of proteins building a functional glycinergic synapse. A notable exception was the enhanced expression of presynaptic glycine transporter 2 (GlyT2), possibly reflecting an adaptation to altered synaptic properties. Super-resolution microscopy revealed rather similar binding of patient-derived aAbs to postsynaptic vs presynaptic sites with individual binding preferences. Although characterization of interneurons showed absence of GlyRα1 in some interneuron subpopulations, GlyRα2 and patient serum signals exhibited a significantly higher colocalization in samples with presynaptic preference. This finding identifies GlyRα2 as the hitherto unknown predominant presynaptic GlyR subunit in the spinal cord and a target of patient aAbs. Whole-cell recordings from glycinergic neurons in mouse brainstem slices underscored the functional relevance of presynaptic aAb binding demonstrated by a significant reduction in the frequency of spontaneous and miniature inhibitory postsynaptic potentials.</p><p><strong>Discussion: </strong>In summary, our study is the first to implicate presynaptic defects in the pathophysiology of autoimmune diseases such as SPS and PERM, which are associated with GlyR aAbs. Individually tuned binding preferences for presynaptic and postsynaptic targets thus underlie the rather diverse appearance of clinical symptoms and different therapeutic responses in patients suffering from GlyR autoimmunity.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200364"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Clinical and Biological Prognostic Factors of Anti-NMDA Receptor Encephalitis in Children.","authors":"Maxime Mazowiecki, Lorraine Flet-Berliac, Julia Roux, Anne Lépine, Pascale Chretien, Salima Hacein-Bey-Abina, Laetitia Giorgi, Frederic Villega, Emmanuel Cheuret, Marie Benaiteau, Veronique Rogemond, Geraldine Picard, Sarah Baer, Pierre Cleuziou, Elodie Lametery, Isabelle Desguerre, Mélodie Aubart, Mathilde Chevignard, Roger Le Grand, Philippe Horellou, Carole Leroy, Bastien Joubert, Jerome Honnorat, Kumaran Deiva","doi":"10.1212/NXI.0000000000200346","DOIUrl":"10.1212/NXI.0000000000200346","url":null,"abstract":"<p><strong>Background and objectives: </strong>Anti-NMDAR encephalitis (NMDARE) is a severe neurologic condition, and recently, the NMDAR Encephalitis One-Year Functional Status (NEOS) score has emerged as a 1-year prognostic tool. This study aimed to evaluate NEOS score and biomarker (neurofilament light chains [NfL], total-Tau protein, glial fibrillary acidic protein, and serum cytokines) correlation with modified Rankin Scale (mRS), cognitive impairment, and clinical recovery in pediatric NMDARE over 2 years.</p><p><strong>Methods: </strong>In this French multicenter observational study, 104 pediatric patients with NMDARE were followed for a minimum of 2 years. Clinical data and serum/plasma samples were collected. Biomarker levels, measured using electroluminescence mesoscale discovery (MSD) S-PLEX, were compared between patients and controls and assessed for correlations with disease activity, mRS, cognitive/language impairment, and recovery status at 2 years.</p><p><strong>Results: </strong>At a median follow-up of 39.5 months, 68 percent of patients had unfavorable recovery and 54% had significant cognitive impairment. Both outcomes were strongly associated with younger age at diagnosis (OR 6.10 [1.91-27.3] <i>p</i> < 0.01 and 5.69 [1.46-27.7] <i>p</i> = 0.02, respectively). A higher NEOS score was significantly correlated with increased cognitive impairment (OR 2.53 [1.52-4.21], <i>p</i> < 0.001), higher mRS scores (OR 2.12 [1.34-3.57], <i>p</i> < 0.01), and unfavorable recovery at 2 years (OR 2.00 [1.30-3.06], <i>p</i> = 0.015). Elevated NfL levels were significantly associated with unfavorable recovery (OR 3.62 [1.29-10.9] <i>p</i> = 0.012) and severe cognitive impairment (OR 3.77 [1.38-10.9] <i>p</i> = 0.012) at 2 years. The combined area under the curve (AUC) for NfL and NEOS was significantly higher than the AUCs of NEOS and NfL alone <i>(p</i> = 0.01).</p><p><strong>Discussion: </strong>The NEOS score strongly predicts long-term outcomes in NMDARE, with its predictive value extending beyond the first-year mR prediction. NfL levels at disease onset seem to improve accuracy in predicting poor outcomes, providing valuable information for treatment decisions and future clinical trials.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200346"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of the Kynurenine Pathway in Relapsing Remitting Multiple Sclerosis and Its Correlations With Progressive Neurodegeneration.","authors":"Ananda Staats Pires, Shivani Krishnamurthy, Samridhi Sharma, Sharron Chow, Samuel Klistorner, Gilles J Guillemin, Alexander Klistorner, Yuyi You, Benjamin Heng","doi":"10.1212/NXI.0000000000200372","DOIUrl":"10.1212/NXI.0000000000200372","url":null,"abstract":"<p><strong>Background and objectives: </strong>Despite the absence of acute lesion activity in multiple sclerosis (MS), chronic neurodegeneration continues to progress, and a potential underlying mechanism could be the kynurenine pathway (KP). Prolonged activation of the KP from chronic inflammation is known to exacerbate the progression of neurodegenerative diseases through the production of neurotoxic metabolites. Among the 8 KP metabolites, six of them, namely kynurenine (KYN), 3-hydroxylkynurenine (3HK), anthranilic acid (AA), kynurenic acid (KYNA), and quinolinic acid (QUIN), have been associated with neurodegeneration.</p><p><strong>Methods: </strong>To gain insights into the links between the KP and neurodegeneration in MS, we investigated the KP metabolomics profile of relapsing remitting MS (RRMS) patients and their correlation with parameters of neurodegeneration in brain and retinal. Outpatients with a clinical diagnosis of RRMS (n = 98) or age-matched and sex-matched healthy controls (n = 39) were included. MS participants undertook yearly evaluation of MRI and optical coherence tomography scan to evaluate neuroaxonal loss. Blood samples were collected at the baseline from all participants for the biochemical analysis of KP metabolites.</p><p><strong>Results: </strong>We identified increased plasma levels of AA and 3HAA in the MS group, indicating an anti-inflammatory response alongside active neurodegeneration. By contrast, plasma levels of KYNA and 3HK were lower in the MS group than in healthy controls. Our analysis revealed a higher KYN:tryptophan (TRP) and QUIN:KYNA ratios in the MS cohort, suggesting activation of the pathway toward the production of neurotoxic QUIN. Another important finding was that KP metabolites were correlated with measures of axonal degeneration in patients with MS. Notably, central brain atrophy positively correlated with the TRP levels, but negatively correlated with KYN and level KYN:TRP ratio. Finally, the choroid plexus volume was inversely correlated with KYNA plasma levels.</p><p><strong>Discussion: </strong>These findings highlight changes in the biosynthesis of KP during the progression of RRMS and its correlation with axonal loss. This study underscores the potential of targeting the KP in developing novel treatments for neuroaxonal damage in MS and warrants future research in greater depth.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200372"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunogenetic Studies in Patients With GAD-Positive Stiff-Person Syndrome Reveal Novel Lymphocytic Genes and <i>KLK10</i>-Gene Variants.","authors":"Popianna Tsiortou, Harry Alexopoulos, Konstantinos Kyriakidis, Michalis Kosmidis, Chrysanthi Barba, Sofia Akrivou, Ioannis Michalopoulos, Panagiotis Politis, Marinos C Dalakas","doi":"10.1212/NXI.0000000000200373","DOIUrl":"10.1212/NXI.0000000000200373","url":null,"abstract":"<p><strong>Background and objectives: </strong>The aim of this study was to identify genetic markers and immunologic characteristics of glutamic acid decarboxylase (GAD) antibody-positive patients with stiff-person syndrome (SPS).</p><p><strong>Methods: </strong>We conducted systemic immunogenetic studies in 11 GAD-positive patients: 8 with sporadic SPS and 3 from a three-generation family with very high GAD-ab titers but diverse symptomatology (one with GAD-epilepsy and SPS and 2 only with diabetes), by performing complete immunologic profile and whole-exome sequencing analysis.</p><p><strong>Results: </strong>Two genes expressed in immune and neuronal tissues were identified: the <i>ORAI1</i> that codes for a calcium release-activated channel protein with a role in the activation of T lymphocytes and the <i>LILRA4</i> that encodes an IgG-like cell surface protein expressed in plasmacytoid dendritic cells. An important finding was the identification of 7 genetic polymorphisms in the novel <i>Kallikrein 10</i> (<i>KLK10)</i> gene, shared by all 9 typical patients with SPS, as verified by Sanger sequencing, but not in the 2 GAD-positive family members with diabetes or the GAD-negative controls. To further verify these findings, Sanger sequencing was performed in 10 more patients with SPS and 15 autoimmune controls collectively confirmed that among a total of 39 tested samples, 95% of the 19 patients with SPS were homozygous or heterozygous for all 7 KLK10 variants while 90% of the 20 controls had the wild type or were heterozygous. <i>KLK10</i> is a peptidase expressed in the choroid plexus epithelium and neuroendocrine organs and participates in the initiation of systemic inflammatory responses and immune-modulated disorders through proteolytic cascades.</p><p><strong>Discussion: </strong>KLK10 is a novel and potentially key genetic marker in patients with SPS that can contribute to disease pathogenesis by altering protease activity or the expression of neuron-to-immune cell signaling facilitating GAD autoimmunity. Along with the 2 newly identified immune-related genes, KLK10 is likely an interplay between genetic predisposition and immune dysregulation, necessitating the need to explore their significance as susceptibility disease factors and possibly as novel therapeutic targets.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200373"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11820810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Manifestations and Treatment Responses in Pediatric Neurofascin 155-IgG4 Autoimmune Nodopathy.","authors":"Hebatallah R Rashed, Naveen Kumar Paramasivan, Duygu Selcen, P James B Dyck, Smathorn Thakolwiboon, Michelle L Mauermann, John Mills, Divyanshu Dubey","doi":"10.1212/NXI.0000000000200368","DOIUrl":"10.1212/NXI.0000000000200368","url":null,"abstract":"<p><strong>Background and objectives: </strong>While it is well characterized in adults, little is known about the clinical features of neurofascin 155-IgG4 autoimmune nodopathy (NF155-IgG4 AN) in the pediatric population. In this study, we aimed to describe the clinical features and treatment outcomes in children diagnosed with neurofascin 155-IgG4 autoimmune nodopathy (NF155-IgG4 AN).</p><p><strong>Methods: </strong>Pediatric and adult patients with NF155-IgG4 AN were identified retrospectively through the Mayo Clinic Neuroimmunology Laboratory database.</p><p><strong>Results: </strong>Eight pediatric and 20 adult patients with NF155-IgG4 AN were included with a median age at onset of 11 and 43 years, respectively. Pediatric patients (3/8) were often diagnosed initially with Guillain-Barre syndrome compared with adults (2/20) (<i>p</i> = 0.123). Six pediatric patients deteriorated beyond 2 months with rapid progression to disease nadir compared with adults (22 vs 52 weeks, <i>p</i> = 0.04). All had distal predominant weakness with paresthesias. Four patients had tremor, and one had cerebellar ataxia. Sensory ataxia was significantly less common in pediatric patients (4/8) compared with adults (18/20) (<i>p</i> = 0.038). Most pediatric patients (6/7) were IVIG refractory and responded to rituximab. Six patients had favorable outcomes after immunotherapy with improvement ≥1 in the Inflammatory Neuropathy Cause and Treatment disability score.</p><p><strong>Discussion: </strong>Pediatric patients with NF155-IgG4 AN display an aggressive disease course with rapid progression to disease nadir compared with adults. Sensory ataxia is less common in children, and they often respond to rituximab. It is crucial to consider autoimmune nodopathies in the differential diagnosis of pediatric patients with suspected inflammatory demyelinating polyneuropathy and to test for NF155-IgG4 antibodies because of their diagnostic and therapeutic implications.</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that in pediatric patients with NF155-IgG4 AN who are refractory to IVIG, rituximab treatment provided some benefit.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200368"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conformational Antibodies to Proteolipid Protein-1 and Its Peripheral Isoform DM20 in Patients With CNS Autoimmune Demyelinating Disorders.","authors":"Stefano Masciocchi, Pietro Businaro, Giacomo Greco, Silvia Scaranzin, Antonio Malvaso, Chiara Morandi, Elisabetta Zardini, Mario Risi, Elisa Vegezzi, Luca Diamanti, Paola Bini, Sabrina Siquilini, Maria Pia Giannoccaro, Luana Morelli, Rocco Liguori, Francesco Patti, Valeria De Giuli, Emilio Portaccio, Chiara Zanetta, Stefania Bergamoni, Anna Maria Simone, Roberta Lanzillo, Giorgia Bruno, Antonio Gallo, Alvino Bisecco, Massimiliano Di Filippo, Flavia Pauri, Antonella Toriello, Paolo Barone, Francesco Tazza, Sebastiano Bucello, Paola Banfi, Martina Fabris, Irene Volonghi, Loredana Raciti, Maria Claudia Vigliani, Tommaso Bocci, Matteo Paoletti, Elena Colombo, Massimo Filippi, Anna Pichiecchio, Enrico Marchioni, Diego Franciotta, Matteo Gastaldi","doi":"10.1212/NXI.0000000000200359","DOIUrl":"10.1212/NXI.0000000000200359","url":null,"abstract":"<p><strong>Background and objectives: </strong>Antibodies to proteolipid protein-1 (PLP1-IgG), a major central myelin protein also expressed in the peripheral nervous system (PNS) as the isoform DM20, have been previously identified mostly in patients with multiple sclerosis (MS), with unclear clinical implications. However, most studies relied on nonconformational immunoassays and included few patients with non-MS CNS autoimmune demyelinating disorders (ADDs). We aimed to investigate conformational PLP1-IgG in the whole ADD spectrum.</p><p><strong>Methods: </strong>We devised a new live cell-based assay (CBA) for PLP1-IgG and used it to test 2 cohorts (retrospective exploratory, n = 284; prospective validation, n = 824) of patients with ADDs and controls (n = 177). Patients were classified as MS, neuromyelitis optica spectrum disorders (NMOSDs), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other ADDs. PLP1-IgG-positive samples were tested for IgG subclasses, DM20-IgG, and on rat brain tissue-based assay (TBA). Complement-dependent cytotoxicity (CDC) was assessed on a live CBA and antigen specificity and conformational binding through immunoadsorption/colocalization/fixation experiments.</p><p><strong>Results: </strong>PLP1-IgG were found in 0 of 177 controls and 42 of 1104 patients with ADDs mainly diagnosed as other ADDs (19/42) with frequent myelitis/encephalomyelitis (14/19) and coexisting PNS involvement (13/19). Four of 19 patients with other ADDs fulfilled the seronegative NMOSD criteria. PLP1-IgG were also found in patients with MOGAD (11/42), more frequently with PNS involvement (<i>p</i> = 0.01), and in patients with MS (12/42), more frequently with atypical features (<i>p</i> < 0.001). PLP1-IgG-positive MOGAD had higher EDSS scores (<i>p</i> < 0.001) and PLP1-IgG-positive MS had higher severity scores (MSSS, <i>p</i> < 0.001) compared with those PLP1-IgG-negative. Overall, PLP1-IgG were found in 24.1% of patients with CNS+PNS-ADD, 21.2% with atypical MS, 8.3% with MOGAD, 12.0% with seronegative NMOSD, and 1.4% with typical MS. Their frequency within each diagnostic subgroup was consistent between the exploratory and validation cohorts. PLP1-IgG a) colocalized with their target on CBA-TBA, where their binding was abolished after immunoadsorption and fixation-induced conformational epitope alteration; b) mostly pertained to the IgG1/IgG3 subclass (68.3%) and were able to induce CDC; and c) coreacted with DM20 in all 12 patients with PNS involvement tested.</p><p><strong>Discussion: </strong>Conformational PLP1-IgG predominantly identify patients with non-MS ADDs. They should be tested mainly in those with CNS + PNS ADD, coherently with DM20-IgG coreactivity. PLP1-IgG could also be investigated as disease modifiers and prognostic markers in MS and MOGAD. Preliminary evidence supports their pathogenic potential.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200359"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}