Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"MIF Tautomerase Inhibition Protects Neurons From Immune-Mediated Cell Death.","authors":"Jackson W Mace, Matthew D Smith, Sachin P Gadani, Marjan Gharagozloo, Valina L Dawson, Ted M Dawson, Peter A Calabresi","doi":"10.1212/NXI.0000000000200568","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200568","url":null,"abstract":"<p><strong>Background and objectives: </strong>Multiple sclerosis (MS) is characterized by peripheral immune cell infiltration into the central nervous system (CNS) and associated reactive gliosis, demyelination, and neuroaxonal degeneration. Existing therapies broadly target adaptive immune cells and treat acute inflammation but are not effective in halting chronic neurodegeneration that occurs in progressive MS. High-efficacy precision therapies that target pathways in the CNS known to contribute to MS pathophysiology are lacking. Several MS studies have identified prominent dysregulation of macrophage migration inhibitory factor (MIF), a multifunctional protein with both cytokine and enzyme activity, in inflammatory diseases. MIF is elevated in the CSF of people with MS and MIF gene variants have been linked with progressive MS, but its precise contributions to the pathophysiologic underpinnings of MS remain unclear. MIF has extracellular signaling capacity through CD74. MIF also has 2 discrete and endogenous enzymatic functions as a tautomerase and nuclease.</p><p><strong>Methods: </strong>We used a MIF transgenic mouse line with a point mutation in the tautomerase domain (MIF-P2G) to dissect MIF's non-nuclease function during inflammation. We also utilized flow cytometry and immunohistochemistry to characterize the cellular and molecular mechanisms by which MIF tautomerase contributes to pathophysiology in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS.</p><p><strong>Results: </strong>We show that MIF tautomerase contributes to immune cell infiltration, glial cell proliferation, and neuroaxonal degeneration in EAE. MIF tautomerase-deficient EAE mice have reduced paralysis scores and less neuroaxonal pathology throughout the optic nerve and lumbar spinal cord. Furthermore, we show that MIF-P2G mutated mice have less peripheral immune cell trafficking and downstream reactive gliosis, neuroinflammation, and neurodegeneration during EAE.</p><p><strong>Discussion: </strong>Together, this work elucidates the role of MIF's tautomerase domain in contributing to peripheral immune-mediated neurodegeneration in the context of neuroinflammatory diseases such as MS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200568"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777175","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":"Real-World Efficacy and Safety of Neuromyelitis Optica Spectrum Disorder Disease-Modifying Treatments.","authors":"Philippe A Bilodeau, Mattia Wruble Clark, Avanteeka Ganguly, Jenna Bernice Harowitz, Joao Vitor Mahler, Mulan Jiang, Sathya S Narasimhan, Danielle Kei Pua, Brian C Healy, Farrah Jasmine Mateen, Michael Levy, Shamik Bhattacharyya","doi":"10.1212/NXI.0000000000200583","DOIUrl":"10.1212/NXI.0000000000200583","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200583"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628106","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":"Vestibular and Ocular Motor Phenotype in a Case of Paraneoplastic Autoimmune Kelch-Like Protein-11 Encephalitis.","authors":"Felix Konstantin Schwarz, Romana Höftberger, Verena Endmayr, Ines Lukac, Paulus S Rommer, Jakob Rath, Thomas Berger, Ivan Milenkovic, Gerald Wiest","doi":"10.1212/NXI.0000000000200576","DOIUrl":"10.1212/NXI.0000000000200576","url":null,"abstract":"<p><strong>Objectives: </strong>KLHL11 encephalitis is often associated with vestibular symptoms and ataxia. However, the specific disorders of the vestibular and oculomotor systems have only been partially investigated so far. We present a case of paraneoplastic KLHL11 encephalitis in which vestibulo-oculomotor function was quantitatively assessed.</p><p><strong>Methods: </strong>A 1.5T MRI scan of the brain and cervical spinal cord was performed. KLHL11 IgG in serum and CSF was detected using a fixed cell-based assay. Vestibulo-oculomotor function was assessed by videooculography with rotational chair tests.</p><p><strong>Results: </strong>MRI scans of the brain and cervical spine were normal. Serum and CSF were strongly positive for KLHL11 antibodies, confirming the diagnosis of KLHL11 encephalitis. Videooculography revealed spontaneous downbeat nystagmus and horizontal gaze-evoked nystagmus bidirectionally, pronounced on left gaze. Smooth pursuit eye movements were saccadic in both directions. Horizontal and vertical saccades showed prolonged latencies, mild dysmetria, and normal saccadic velocities. In the rotational tests, the vestibulo-ocular reflex (VOR) was symmetrical at all frequencies and exhibited a normal to high-normal gain. The VOR fixation-suppression during sinusoidal rotation was almost abolished.</p><p><strong>Discussion: </strong>Our clinical neurophysiologic data imply that KLHL11 encephalitis is characterized by a pronounced vestibulo-cerebellar syndrome, which places it among the few autoimmune encephalitides with this specific phenotype.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200576"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628195","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":"Emerging CSF and Serum Biomarkers in Multiple Sclerosis: Cytokines, MOG, GFAP, and Beyond.","authors":"Johanna Oechtering, Sabine Anna Schaedelin, Aleksandra Maleska Maceski, Kerstin Stein, Nafiye Genc, Maximilian Einsiedler, Pascal Benkert, Eline Willemse, Tobias J Derfuss, Bettina Fischer-Barnicol, Marcus D'Souza, Axel Regeniter, Wayne Hu, Ferhan Qureshi, Sebastian Finkener, Stefanie Mueller, Robert Hoepner, Patrice H Lalive, Caroline Pot, Claudio Gobbi, Chiara Zecca, Patrick Roth, Heinz Wiendl, Jan D Lünemann, Ludwig Kappos, Cristina Granziera, David Leppert, Jens Kuhle","doi":"10.1212/NXI.0000000000200578","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200578","url":null,"abstract":"<p><strong>Background and objectives: </strong>Accurate biomarkers that reflect disease activity, severity, and molecular pathophysiology in multiple sclerosis (MS) remain an unmet diagnostic need. We compared the performance of the established biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), with emerging candidates in CSF and serum.</p><p><strong>Methods: </strong>We measured 21 analytes using Olink proximity extension assay technology, NfL and GFAP using Simoa, and soluble triggering receptor expressed on myeloid cells (sTREM2) and neuronal pentraxin 2 (NPTX2) using Fujirebio platforms in paired CSF and serum/plasma samples from 293 participants. The cohort included patients with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS), as well as individuals with inflammatory neurologic disease and symptomatic controls (SCs). CSF and serum biomarker levels were compared across diagnostic groups using multivariable Cox and linear regression models. Associations were assessed using CSF immunoglobulin profiles, time from first to second clinical event, and Expanded Disability Status Scale (EDSS) scores in CIS, as well as the Multiple Sclerosis Severity Score (MSSS) in patients with MS.</p><p><strong>Results: </strong>Eight biomarkers showed consistent differential expression. In CSF, CXCL13, CXCL9, IL-12b, and NfL were elevated in most CIS and MS subgroups compared with SCs. Osteopontin (OPN) levels were increased in RRMS and PPMS subgroups, whereas TNFRSF10A elevations were confined to patients with PPMS. In serum, NfL was elevated across all CIS and MS subgroups, GFAP was increased in RRMS and SPMS subgroups, and myelin oligodendrocyte glycoprotein (MOG) was increased in RRMS and PPMS subgroups. Higher CSF levels of CXCL13, CXCL9, and IL-12b predicted shorter intervals to a second clinical attack and correlated strongly with intrathecal IgM synthesis. Elevated EDSS scores at CIS onset were linked to higher CSF levels of CXCL13, IL-12b, TNFRSF10A, and OPN, and to NfL, GFAP, and MOG in serum. Prediction of future MSSS was limited to GFAP in CSF, whereas in serum, GFAP, MOG, OPN, and CXCL9 were significantly associated.</p><p><strong>Discussion: </strong>CSF CXCL13, CXCL9, and IL-12b are promising biomarkers for predicting relapse activity, while serum GFAP and MOG appear to be consistent candidates for prognosticating disease severity.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200578"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777574","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 Features and Biomarkers Associated With Intensive Care-Dependent Refractory NMDAR Encephalitis: A Retrospective Cohort Study.","authors":"Iker Elosua-Bayes, Pauline Dumez, Marie Benaiteau, Nicolás Lundahl Ciano-Petersen, Antonio Farina, Macarena Villagrán-García, Elise Peter, Cristina Birzu, Anthony Fourier, Mélodie Aubart, Geraldine Picard, Le Duy Do, Véronique Rogemond, David Goncalves, Dimitri Psimaras, Jerome Honnorat, Bastien Joubert","doi":"10.1212/NXI.0000000000200552","DOIUrl":"10.1212/NXI.0000000000200552","url":null,"abstract":"<p><strong>Background and objectives: </strong>A subset of patients with NMDAR encephalitis is resistant to first-line and second-line immunotherapy and requires prolonged intensive care. The clinical definition of refractory, intensive care-dependent NMDARE (RI-NMDARE) is lacking, and its frequency, risk factors, and outcomes are unknown. The aim of this study was to define RI-NMDARE and compare its clinical and biomarker characteristics with those of severe NMDARE.</p><p><strong>Methods: </strong>This was a retrospective cohort study including patients with nonherpetic NMDARE admitted to intensive care units (ICUs) and diagnosed at the French National Reference Center, from 2005 to 2023. Favorable outcome was defined as a modified Rankin Scale (mRS) score < 2 at 24 months from onset.</p><p><strong>Results: </strong>The study included 216 ICU-admitted patients with NMDARE (81% female, median age 21 years). Nearly 90% of patients were discharged from ICU within 3 months after initiation of second-line therapy; the remainder were defined as patients with RI-NMDARE (26/216 patients, 12%; 92% female; median age, 24 years-none younger than 15 years; median ICU stay, 5.7 months). Compared with the rest of the cohort, patients with RI-NMDARE were more frequently of non-White ethnicity (14/25, 56%, vs 55/156, 35%; <i>p</i> = 0.047) and had more frequent mechanical ventilation (26/26, 100%, vs 116/183, 63%; <i>p</i> < 0.001); ovarian teratoma (62% vs 22%, <i>p</i> < 0.001); and combination of seizures, hyperkinetic movement disorders, and dysautonomia (85% vs 33%, <i>p</i> < 0.001). They also had shorter times from onset to ICU admission (median 7 vs 14 days; <i>p</i> = 0.002) and significantly higher median CSF cell counts (72 vs 25/mm³, <i>p</i> < 0.001), CSF antibody titers (1,280 vs 60, <i>p</i> < 0.001), and serum neurofilament levels (230 vs 144 pg/mL, <i>p</i> = 0.028). Despite increased use of the cyclophosphamide-rituximab combination (85% vs 17%, <i>p</i> < 0.001) and earlier immunotherapy (median 10 days, range 1-82 vs 19 days, range 1-304; <i>p</i> = 0.001), patients with RI-NMDARE had poorer outcomes (mRS score ≥ 2 at 24 months, 72% vs 39%; <i>p</i> = 0.004) and higher mortality (19% vs 6.7%, <i>p</i> = 0.046) compared with non-RI-NMDARE patients.</p><p><strong>Discussion: </strong>RI-NMDARE represents a distinct, high-risk subgroup with a severe clinical profile marked by rapid disease progression; the triad of seizures, movement disorders, and dysautonomia; and elevated biomarkers. RI-NMDARE is associated with poorer outcomes, underscoring the need for early recognition and tailored therapeutic strategies.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200552"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12910818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195063","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":"miRNA Signature in CSF From Patients With Primary Progressive Multiple Sclerosis.","authors":"María Muñoz-San Martín, Imma Gómez, Ana Quiroga-Varela, Marina Gonzalez-Del Río, René Robles Cedeño, Gary Álvarez, Maria Buxó, Albert Miguela, Luisa María Villar, Jessica Castillo-Villalba, Bonaventura Casanova, Ester Quintana, Lluís Ramió-Torrentà","doi":"10.1212/NXI.0000000000200569","DOIUrl":"10.1212/NXI.0000000000200569","url":null,"abstract":"","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200569"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12910817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195105","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":"Rapidly Progressive and Relapsing Myelitis With Human T Lymphotropic Virus Type 1: A Case Report and Review of the Literature.","authors":"Andrew A Morrison, Rohini D Samudralwar, Joseph R Berger","doi":"10.1212/NXI.0000000000200570","DOIUrl":"10.1212/NXI.0000000000200570","url":null,"abstract":"<p><p>A patient presented to our center in the northeastern United States with recurrent longitudinally extensive myelitis which was ultimately attributed to infection with human T lymphotropic virus type 1 (HTLV-1). The most common neurologic presentation of this infection is an insidiously progressive myelopathy, although reports of rapid progression with acute onset have been described, including some associated with inflammatory changes on spinal cord MRI. Here, we describe a case of this rare entity and provide a review of the clinical, diagnostic, and treatment data of similar published cases. Along with our case, 44 published cases of rapidly progressive or relapsing HTLV-1-associated myelopathy (HAM) were identified and included in this review. Patients were predominantly female and from Japan, the Caribbean, or South America with a median time from clinical onset to presentation of 5 months. There were radiographic features of myelitis in 98% of patients, with 93% showing longitudinally extensive lesions and only 1 patient with normal spinal MRI. Most patients received steroid therapy and 94% of patients experienced symptomatic or radiographic improvement after treatment, although longitudinal follow-up of these patients was limited. In summary, HAM may present as a rapidly progressive or relapsing myelitis. Patients with acute myelitis should be tested for HTLV-1 infection, especially in cases of longitudinally extensive myelitis with relevant exposure risk factors and negative testing for alternate diagnoses. Although these patients often experience clinical and radiographic improvement with steroid therapy, further work is needed to clarify whether this treatment influences chronic disease progression.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200570"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13075422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531424","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":"CSF Proteins Associated With Neuroaxonal Damage in Early Active Multiple Sclerosis.","authors":"Felix Luessi, Chiara Starvaggi Cucuzza, Sinah Engel, Arda Civelek, Falk Steffen, Thomas Koeck, Philipp S Wild, Ingrid Kockum, Tomas Olsson, Stefan Bittner, Fredrik Piehl, Frauke Zipp","doi":"10.1212/NXI.0000000000200564","DOIUrl":"10.1212/NXI.0000000000200564","url":null,"abstract":"<p><strong>Background and objectives: </strong>The aim of this study was to identify biological processes associated with neuroaxonal degeneration in multiple sclerosis (MS) by analyzing protein patterns linked to neurofilament light (NfL) protein in CSF and serum samples.</p><p><strong>Methods: </strong>The highly sensitive proximity extension assay technology was used to quantify protein levels in paired CSF and serum samples from treatment-naïve, early-stage active MS patients (n = 114). The cohort was stratified into above and below median of CSF-NfL level. A discovery phase identified proteins upregulated in CSF, and a validation cohort (n = 128) confirmed findings in a more clinically diverse MS population, including patients receiving disease-modifying therapies.</p><p><strong>Results: </strong>In the discovery cohort, 13 proteins were upregulated in CSF (leukocyte immunoglobulin like receptor B4, CXCL6, CXCL5, cluster of differentiation 38, CCL19, CXCL11, IMPA1, macrophage scavenger receptor 1 (MSR1), CXCL10, monocyte chemotactic protein 2, ITM2A, TNFRSF12A, and CCL23). It is important to note that associations with CCL19, CXCL11, MSR1, CXCL10, TNFRSF12A, and CCL23 were replicated in a validation MS cohort. By contrast, no consistent serum protein profiles associated with serum levels of NfL could be discerned in this group-based analysis. Furthermore, 75 CSF proteins showed a positive adjusted linear association with CSF-NfL, whereas no such significant association remained in the corresponding analysis in serum.</p><p><strong>Discussion: </strong>The identified and replicated CSF protein profile indicates distinct inflammatory processes associated with ongoing neuroaxonal degeneration. All of these most robust 6 proinflammatory markers-CCL19, CXCL11, MSR1, CXCL10, TNFRSF12A, and CCL23-independently replicated and were individually observed to be relevant in the context of MS. These findings may further elucidate the immunologic pathways underlying disease processes leading to neuroaxonal degeneration.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200564"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513816","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":"HLA Associations Differ by Ethnicity and Aquaporin-4 Antibody Status in Patients With Neuromyelitis Optica Spectrum Disorders.","authors":"Moritz Niederschweiberer, Georgia Panagiotaropoulou, Marcelo A Fernandez-Viña, Gonzalo Montero-Martin, Kazutoyo Osoegawa, Megan Behne, Andre Franke, Wolfgang Lieb, Sven Jarius, Brigitte Wildemann, Patrick Schindler, Carolin Otto, Friedemann Paul, Eoin P Flanagan, Lawrence J Cook, Jorge Oksenberg, Michael R Yeaman, Stephan Ripke, Klemens Ruprecht","doi":"10.1212/NXI.0000000000200562","DOIUrl":"10.1212/NXI.0000000000200562","url":null,"abstract":"<p><strong>Background and objectives: </strong>Neuromyelitis optica spectrum disorders (NMOSDs) comprise inflammatory processes of the CNS. Most patients with NMOSD have serum immunoglobulin (Ig) G autoantibodies directed against the astrocytic water channel aquaporin-4 (AQP4-IgG). In this study, we analyzed HLA allelic frequencies in a large cohort of patients with NMOSD, stratified by ethnicity and AQP4-IgG status, compared with healthy controls.</p><p><strong>Methods: </strong>Next-generation sequencing-based HLA class I and II genotyping was performed in 174 White, 45 Black, and 41 Hispanic AQP4-IgG-positive (AQP4-IgG+) patients with NMOSD; 49 White patients with AQP4-IgG-negative (AQP4-IgG-) NMOSD; and 2,427 White, 244 Black, and 155 Hispanic controls. Correction for multiple testing was performed using the Bonferroni method.</p><p><strong>Results: </strong>In White AQP4-IgG+ patients with NMOSD, the most significantly associated alleles were <i>HLA-DQA1*05:01:01</i> (30.1% vs 11.1%, odds ratio 3.43 [95% CI 2.65-4.42], corrected <i>p</i> = 8.95E-17), <i>HLA-DQB1*02:01:01</i> (29.9% vs 11.3%, 3.34 [2.58-4.31], corrected <i>p</i> = 4.33E-16), and <i>HLA-DRB1*03:01:01</i> (29.2% vs 11.6%, 3.15 [2.43-4.06], corrected <i>p</i> = 3.66E-14), followed by <i>HLA-B*08:01:01</i> (26% vs 10.4%, 3.02 [2.3-3.94] corrected <i>p</i> = 8.79E-12), <i>HLA-C*07:01:01</i> (27.8% vs 14%, 2.36 [1.81-3.04], corrected <i>p</i> = 2.44E-07), and <i>HLA-DRB3*01:01:02</i> (28% vs 14.7%, 2.27 [1.73-2.95], corrected <i>p</i> = 2.19E-06). The frequency of <i>HLA-DRB1*08:04:01</i> was higher in Black AQP4-IgG+ patients with NMOSD than in Black controls but did not achieve statistical significance (19.3% vs 5.7%, 3.92 [1.91-7.86], corrected <i>p</i> = 0.08). Nevertheless, when compared with a larger cohort of Black controls (n = 16,178), the frequency of <i>HLA-DRB1*08:04</i> (19.3% vs 5.1%, 4.46 [2.45-7.66], corrected <i>p</i> = 1.88E-03) was significantly higher in Black AQP4-IgG+ patients with NMOSD. No significant HLA associations were detected in AQP4-IgG+ Hispanic patients or White AQP4-IgG- patients with NMOSD.</p><p><strong>Discussion: </strong>This study confirms the previously recognized association of <i>HLA-DRB1*03:01</i> with AQP4-IgG+ NMOSD in White patients and extends this association to the <i>HLA-DRB1*03:01:01</i>∼<i>HLA-DQA1*05:01:01</i>∼<i>HLA-DQB1*02:01:01</i> haplotype. Furthermore, it identifies an association of <i>HLA-DRB1*08:04</i> with AQP4-IgG+ NMOSD in Black patients. However, no HLA associations were detected in White AQP4-IgG- patients with NMOSD. The immunogenetic differences between AQP4-IgG+ and AQP4-IgG- NMOSD support pathophysiologic distinctions between these entities.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200562"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13088193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699347","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":"Low Prevalence and Inconsistency of LRP4-IgG Detection in Suspected Myasthenia Gravis: A Multicenter CBA Comparison.","authors":"Ilaria Gligora, Pietro Businaro, Lucrezia Serra, Silvia De Pasqua, Fortuna Ricciardiello, Luana Morelli, Chiara Morandi, Stefano Masciocchi, Antonio Malvaso, Corrado Ballestracci, Vitantonio Di Stasi, Veria Vacchiano, Anna Fetta, Simone Rossi, Keivan Kaveh Moghadam, Giovanni Rizzo, Domenica Chiara Milano, Andrea Zini, Duccio Maria Cordelli, Rita Rinaldi, Vincenzo Donadio, Rocco Liguori, Matteo Gastaldi, Maria Pia Giannoccaro","doi":"10.1212/NXI.0000000000200554","DOIUrl":"10.1212/NXI.0000000000200554","url":null,"abstract":"<p><strong>Background and objectives: </strong>Myasthenia gravis (MG) is an autoimmune disorder primarily caused by antibodies targeting neuromuscular junction proteins, particularly the acetylcholine receptor and the muscle-specific tyrosine kinase. However, 10%-20% of patients with MG are double-seronegative (dsMG). Antibodies against low-density lipoprotein receptor-related protein 4 (LRP4-IgG) have been found in a variable proportion of dsMG cases, but their frequency and clinical relevance remain unclear because of differences in assay methodologies and study populations. In this study, we assessed the frequency of LRP4-IgG in patients with suspected MG using different cell-based assay (CBA) protocols.</p><p><strong>Methods: </strong>In this multicenter observational study, we enrolled consecutive patients presenting with symptoms suggestive of MG. LRP4-IgG was tested by 2 centers using 3 different CBAs: live (l-CBA), methanol-fixed (mf-CBA), and paraformaldehyde-fixed (pf-CBA). Patients were classified as having MG or other disorders (ODs). Positive samples were cross-tested between centers.</p><p><strong>Results: </strong>Among 684 patients (302 with MG, 382 with ODs), LRP4-IgG was detected by mf-CBA in 2% (6/302) of MG cases and in 0.52% (2/382) of OD cases. Among patients with MG, 3.9% (4/102) of dsMG and 1% (2/200) of seropositive patients tested positive. Only 50% of mf-CBA-positive cases were confirmed by pf-CBA, and none were detected by l-CBA. Cross-center testing showed partial reproducibility.</p><p><strong>Discussion: </strong>LRP4-IgG detection in suspected MG is rare and inconsistent across assays, suggesting that routine testing is not currently warranted and that these antibodies are at present of limited diagnostic value. These findings highlight the need for standardized, validated LRP4-IgG assays. Future studies should focus on direct comparison and harmonization of testing protocols to clarify the clinical utility of LRP4-IgG testing.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"13 3","pages":"e200554"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12931517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146258870","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}