{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T01:13:15Z","timestamp":1793841195921,"version":"4.6.1"},"reference-count":131,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>A significant subset of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases occurs as a paraneoplastic syndrome, where an underlying tumor triggers a devastating autoimmune attack against the central nervous system. This autoimmune response is driven by pathogenic aquaporin-4 autoantibodies (AQP4-IgG), likely initiated by the tumor\u2019s expression of AQP4 in a phenomenon of molecular mimicry. Understanding the precise immune mechanisms that link a patient\u2019s cancer to their neurological disease is critical for early diagnosis of the occult malignancy and for improved patient outcomes. This review explores how multi-omics technologies are revolutionizing the investigation of T and B cell functional dynamics in this specific context, offering unprecedented resolution into the pathogenesis of paraneoplastic NMOSD. The application of integrated multi-omics\u2014including genomics, epigenomics, transcriptomics (particularly single-cell RNA-seq), proteomics, and metabolomics\u2014provides a holistic framework to dissect the specific immune response directed against both the tumor and the CNS. Transcriptomics, notably scRNA-seq, can deconstruct the heterogeneity of tumor-infiltrating and circulating T and B cells to identify the pathogenic subsets responsible for the autoimmune pathology. Proteomics can aid in identifying tumor-specific biomarkers, while metabolomics offers insights into the metabolic vulnerabilities of the autoreactive immune cells. Multi-omics analyses reveal the cellular and molecular cascade of the paraneoplastic response. High-throughput T-cell receptor (TCR) and B-cell receptor (BCR) sequencing provides direct evidence of oligoclonal expansions, identifying the specific T and B cell clones that likely recognize shared AQP4 epitopes on both the cancer cells and CNS astrocytes. These expanded B cells show hallmarks of a mature, antigen-driven response, including class-switching and affinity maturation of the pathogenic AQP4-IgG. Furthermore, analyses of T cell dynamics reveal a pro-inflammatory environment, with functional impairment of regulatory T cells (Tregs) and a skewed balance towards Th17 and Th1 cells, which is likely initiated by the tumor and perpetuated in the CNS via critical T-B cell interactions, such as the IFN-I \u2192 B-cell \u2192 IL-6 \u2192 pathogenic Th17 axis. Despite these insights, substantial challenges remain in translating these findings into clinical practice. A key hurdle is using multi-omics to develop a reliable molecular signature that can distinguish paraneoplastic from idiopathic NMOSD at diagnosis, thereby streamlining cancer screening for high-risk patients. Advanced computational tools, including AI and machine learning, are needed to integrate the immense volume of data and identify the subtle differences. Future research must prioritize the analysis of longitudinal samples (before and after tumor treatment) and the functional validation of the identified pathogenic pathways. In conclusion, multi-omics is profoundly enhancing our understanding of how tumors can initiate and sustain a specific, targeted autoimmune response in paraneoplastic NMOSD. This deep mechanistic investigation not only promises to improve diagnostics and personalized therapies for these complex patients but also serves as a powerful model for understanding other paraneoplastic syndromes, ultimately bridging the fields of oncology and neuroimmunology.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1665688","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T05:34:14Z","timestamp":1756791254000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Decoding paraneoplastic neuromyelitis optica: a multi-omics investigation of tumor-driven T and B cell dynamics"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenjing","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyi","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichun","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30392-6","article-title":"New therapies for neuromyelitis optica spectrum disorder","volume":"20","author":"Levy","year":"2021","journal-title":"Lancet Neurol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.53.5.1107","article-title":"The clinical course of neuromyelitis optica (Devic\u2019s syndrome)","volume":"53","author":"Wingerchuk","year":"1999","journal-title":"Neurology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001367","article-title":"MRI characteristics of neuromyelitis optica spectrum disorder: An international update","volume":"84","author":"Kim","year":"2015","journal-title":"Neurology"},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1016\/j.jns.2015.08.022","article-title":"Devic\u2019s disease before Devic: Bilateral optic neuritis and simultaneous myelitis in a young woman (1874)","volume":"358","author":"Jarius","year":"2015","journal-title":"J Neurological Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awf151","article-title":"A role for humoral mechanisms in the pathogenesis of Devic\u2019s neuromyelitis optica","volume":"125","author":"Lucchinetti","year":"2002","journal-title":"Brain"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318214332c","article-title":"Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic implications","volume":"76","author":"Popescu","year":"2011","journal-title":"Neurology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001729","article-title":"International consensus diagnostic criteria for neuromyelitis optica spectrum disorders","volume":"85","author":"Wingerchuk","year":"2015","journal-title":"Neurology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.5699","article-title":"Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy","volume":"71","author":"Mealy","year":"2014","journal-title":"JAMA Neurol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02249-1","article-title":"Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies","volume":"18","author":"Carnero Contentti","year":"2021","journal-title":"J Neuroinflamm"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2011.03529.x","article-title":"The prevalence of neuromyelitis optica in South East Wales","volume":"19","author":"Cossburn","year":"2012","journal-title":"Eur J Neurol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.743798","article-title":"Paraneoplastic neuromyelitis optica spectrum disorder associated with lung adenocarcinoma: A case report","volume":"8","author":"Maiorca","year":"2021","journal-title":"Front Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.jns.2023.120825","article-title":"Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder in a paraneoplastic context","volume":"454","author":"Hyun","year":"2023","journal-title":"J Neurol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517731914","article-title":"Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies","volume":"24","author":"Sep\u00falveda","year":"2017","journal-title":"Multiple Sclerosis J"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-021-05055-y","article-title":"Paraneoplastic neuromyelitis optica spectrum disorders: a case series","volume":"42","author":"Virgilio","year":"2021","journal-title":"Neurol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2174\/157015911796557948","article-title":"Idiopathic transverse myelitis and neuromyelitis optica: clinical profiles, pathophysiology and therapeutic choices","volume":"9","author":"Awad","year":"2011","journal-title":"Curr Neuropharmacol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.5761\/atcs.cr.20-00354","article-title":"Paraneoplastic neuromyelitis optica spectrum disorder associated with atypical thymic carcinoid: A case report","volume":"28","author":"Mitsui","year":"2021","journal-title":"Ann Thorac Cardiovasc Surg"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2021.103227","article-title":"Neuromyelitis optica spectrum disorder (NMOSD) associated with cancer: A systematic review","volume":"56","author":"Shahmohammadi","year":"2021","journal-title":"Mult Scler Relat Disord"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)17551-X","article-title":"A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis","volume":"364","author":"Lennon","year":"2004","journal-title":"Lancet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050304","article-title":"IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel","volume":"202","author":"Lennon","year":"2005","journal-title":"J Exp Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm047","article-title":"Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis","volume":"130","author":"Misu","year":"2007","journal-title":"Brain"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70133-3","article-title":"Aquaporin 4 and neuromyelitis optica","volume":"11","author":"Papadopoulos","year":"2011","journal-title":"Lancet Neurol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318248dec1","article-title":"Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays","volume":"78","author":"Waters","year":"2012","journal-title":"Neurology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11910-z","article-title":"Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management","volume":"271","author":"K\u00fcmpfel","year":"2024","journal-title":"J Neurol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000289761.64862.ce","article-title":"Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica","volume":"69","author":"Hinson","year":"2007","journal-title":"Neurology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp309","article-title":"Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice","volume":"133","author":"Saadoun","year":"2010","journal-title":"BRAIN"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22551","article-title":"Ex vivo spinal cord slice model of neuromyelitis optica reveals novel immunopathogenic mechanisms","volume":"70","author":"Zhang","year":"2011","journal-title":"Ann Neurol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.06.085","article-title":"Neuromyelitis optica: Passive transfer to rats by human immunoglobulin","volume":"386","author":"Kinoshita","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"B28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fneur.2021.703249","article-title":"An experimental model of neuromyelitis optica spectrum disorder-optic neuritis: insights into disease mechanisms","volume":"12","author":"Soerensen","year":"2021","journal-title":"Front Neurol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.6331","article-title":"Paraneoplastic neuromyelitis optica spectrum disorder associated with metastatic carcinoid expressing aquaporin-4","volume":"71","author":"Figueroa","year":"2014","journal-title":"JAMA Neurol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2017.10.030","article-title":"Paraneoplastic neuromyelitis optica spectrum disorder: A case report and review of the literature","volume":"48","author":"Annus","year":"2018","journal-title":"J Clin Neurosci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000101","article-title":"Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders","volume":"82","author":"Sato","year":"2014","journal-title":"Neurology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31826aac4e","article-title":"Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype","volume":"79","author":"Kitley","year":"2012","journal-title":"Neurology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41582-018-0112-x","article-title":"Myelin oligodendrocyte glycoprotein antibodies in neurological disease","volume":"15","author":"Reindl","year":"2019","journal-title":"Nat Rev Neurol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11634-0","article-title":"Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis","volume":"270","author":"Jarius","year":"2023","journal-title":"J Neurol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00415-013-7169-7","article-title":"Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS)","volume":"261","author":"Trebst","year":"2014","journal-title":"J Neurol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1900866","article-title":"Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder","volume":"381","author":"Pittock","year":"2019","journal-title":"New Engl J Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30078-8","article-title":"Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomized, double-blind, multicenter, placebo-controlled phase 3 trial","volume":"19","author":"Traboulsee","year":"2020","journal-title":"Lancet Neurol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0322098","article-title":"Potential drug targets for Neuromyelitis optica spectrum disorders (NMOSD): A Mendelian randomization analysis","volume":"20","author":"Meng","year":"2025","journal-title":"PloS One"},{"key":"B39","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41582-021-00498-5","article-title":"B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies","volume":"17","author":"Cencioni","year":"2021","journal-title":"Nat Rev Neurol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017385108","article-title":"Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica","volume":"108","author":"Chihara","year":"2011","journal-title":"Proc Natl Acad Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.783304","article-title":"Can immune tolerance be re-established in neuromyelitis optica","volume":"12","author":"Loda","year":"2021","journal-title":"Front Neurol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2011.01.031","article-title":"Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse","volume":"18","author":"Wang","year":"2011","journal-title":"J Clin Neurosci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/nyas.12118","article-title":"Immunology of neuromyelitis optica: a T cell-B cell collaboration","volume":"1283","author":"Mitsdoerffer","year":"2013","journal-title":"Ann N Y Acad Sci"},{"key":"B44","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1002\/ana.23651","article-title":"Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter","volume":"72","author":"Varrin-Doyer","year":"2012","journal-title":"Ann Neurol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.msard.2015.12.004","article-title":"T-cell responses to distinct AQP4 peptides in patients with neuromyelitis optica (NMO)","volume":"6","author":"Vaknin-Dembinsky","year":"2016","journal-title":"Multiple sclerosis related Disord"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07079-8","article-title":"B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4","volume":"627","author":"Afzali","year":"2024","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1322125","article-title":"Single-cell RNA sequencing reveals cell type-specific immune regulation associated with human neuromyelitis optica spectrum disorder","volume":"15","author":"Jiang","year":"2024","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2014.11.011","article-title":"Association of circulating follicular helper T cells with disease course of NMO spectrum disorders","volume":"278","author":"Li","year":"2015","journal-title":"J Neuroimmunology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1186\/s12967-024-05801-8","article-title":"Integrated omics profiling reveals systemic dysregulation and potential biomarkers in the blood of patients with neuromyelitis optica spectrum disorders","volume":"22","author":"Xie","year":"2024","journal-title":"J Transl Med"},{"key":"B50","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nri.2017.76","article-title":"Single-cell RNA sequencing to explore immune cell heterogeneity","volume":"18","author":"Papalexi","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.coisb.2019.03.003","article-title":"Systems immunology: Integrating multi-omics data to infer regulatory networks and hidden drivers of immunity","volume":"15","author":"Yu","year":"2019","journal-title":"Curr Opin Syst Biol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/1177932219899051","article-title":"Multi-omics data integration, interpretation, and its application","volume":"14","author":"Subramanian","year":"2020","journal-title":"Bioinf Biol Insights"},{"key":"B53","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/nrg.2018.4","article-title":"Integrative omics for health and disease","volume":"19","author":"Karczewski","year":"2018","journal-title":"Nat Rev Genet"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12122750","article-title":"Revolutionizing personalized medicine: synergy with multi-omics data generation, main hurdles, and future perspectives","volume":"12","author":"Molla","year":"2024","journal-title":"Biomedicines"},{"key":"B55","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s13059-017-1215-1","article-title":"Multi-omics approaches to disease","volume":"18","author":"Hasin","year":"2017","journal-title":"Genome Biol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"106359","DOI":"10.1016\/j.isci.2023.106359","article-title":"Integrative multi-omics approaches to explore immune cell functions: Challenges and opportunities","volume":"26","author":"Wang","year":"2023","journal-title":"iScience"},{"key":"B57","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/nrg3868","article-title":"Methods of integrating data to uncover genotype-phenotype interactions","volume":"16","author":"Ritchie","year":"2015","journal-title":"Nat Rev Genet"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.52033","article-title":"Identification of potential biomarkers for neuromyelitis optica by quantitative proteomics","volume":"11","author":"Ding","year":"2024","journal-title":"Ann Clin Transl Neurol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.semcancer.2022.12.009","article-title":"Artificial intelligence-based multi-omics analysis fuels cancer precision medicine","volume":"88","author":"He","year":"2023","journal-title":"Semin Cancer Biol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"343919","DOI":"10.1016\/j.aca.2025.343919","article-title":"Development of disease diagnosis technology based on coattention cross-fusion of multiomics data","volume":"1351","author":"Wu","year":"2025","journal-title":"Analytica Chimica Acta"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/nature19949","article-title":"Mass-spectrometric exploration of proteome structure and function","volume":"537","author":"Aebersold","year":"2016","journal-title":"Nature"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.690537","article-title":"Multi-level analyses of genome-wide association study to reveal significant risk genes and pathways in neuromyelitis optica spectrum disorder","volume":"12","author":"Li","year":"2021","journal-title":"Front Genet"},{"key":"B63","doi-asserted-by":"publisher","first-page":"100776","DOI":"10.1016\/j.xgen.2025.100776","article-title":"Contribution of germline and somatic mutations to risk of neuromyelitis optica spectrum disorder","volume":"5","author":"Yata","year":"2025","journal-title":"Cell Genomics"},{"key":"B64","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/s41598-020-80535-3","article-title":"Neuromyelitis optica is an HLA associated disease different from Multiple Sclerosis: a systematic review with meta-analysis","volume":"11","author":"Alvarenga","year":"2021","journal-title":"Sci Rep"},{"key":"B65","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1038\/s41467-018-04332-3","article-title":"A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica","volume":"9","author":"Estrada","year":"2018","journal-title":"Nat Commun"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182190f74","article-title":"A population-based study of neuromyelitis optica in Caucasians","volume":"76","author":"Asgari","year":"2011","journal-title":"Neurology"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501016","article-title":"Signal strength and metabolic requirements control cytokine-induced th17 differentiation of uncommitted human T cells","volume":"195","author":"Kastirr","year":"2015","journal-title":"J Immunol"},{"key":"B68","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/nrg.2016.59","article-title":"The molecular hallmarks of epigenetic control","volume":"17","author":"Allis","year":"2016","journal-title":"Nat Rev Genet"},{"key":"B69","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/hdy.2010.54","article-title":"Epigenetics and gene expression","volume":"105","author":"Gibney","year":"2010","journal-title":"Heredity"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-023-01162-9","article-title":"Transcriptional regulation of autophagy and its implications in human disease","volume":"30","author":"Lei","year":"2023","journal-title":"Cell Death Differentiation"},{"key":"B71","first-page":"592019","article-title":"Multiomics analysis of narcolepsy T cells: global hypomethylation in solo-WCGW motif linked to T cell proliferation","author":"Shimada","year":"2024","journal-title":"bioRxiv"},{"key":"B72","doi-asserted-by":"publisher","first-page":"e1612","DOI":"10.1371\/journal.pone.0001612","article-title":"FOXP3 promoter demethylation reveals the committed treg population in humans","volume":"3","author":"Janson","year":"2008","journal-title":"PloS One"},{"key":"B73","doi-asserted-by":"publisher","first-page":"e79064","DOI":"10.1371\/journal.pone.0079064","article-title":"Downregulation of IFNG in CD4(+) T cells in lung cancer through hypermethylation: a possible mechanism of tumor-induced immunosuppression","volume":"8","author":"Wang","year":"2013","journal-title":"PloS One"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0206-z","article-title":"Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion","volume":"37","author":"Satpathy","year":"2019","journal-title":"Nat Biotechnol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2010.03.015","article-title":"Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-Seq analysis","volume":"6","author":"Tang","year":"2010","journal-title":"Cell Stem Cell"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01351-y","article-title":"Liquid biopsy: current technology and clinical applications","volume":"15","author":"Nikanjam","year":"2022","journal-title":"J Hematol Oncol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3390\/cells14070539","article-title":"Decoding B cells in autoimmune diseases through scRNA + BCR-seq: current knowledge and future directions","volume":"14","author":"Quan","year":"2025","journal-title":"Cells"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.418","article-title":"CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder","volume":"4","author":"Kowarik","year":"2017","journal-title":"Ann Clin Transl Neurol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-023-00809-y","article-title":"Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease","volume":"19","author":"Piwecka","year":"2023","journal-title":"Nat Rev Neurol"},{"key":"B80","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s43556-023-00144-0","article-title":"Spatial transcriptomics in development and disease","volume":"4","author":"Zhou","year":"2023","journal-title":"Mol Biomedicine"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000841","article-title":"Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology","volume":"7","author":"Fujihara","year":"2020","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B82","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhl\u00e9n","year":"2015","journal-title":"Science"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181e2414b","article-title":"Astrocytic damage is far more severe than demyelination in NMO: a clinical CSF biomarker study","volume":"75","author":"Takano","year":"2010","journal-title":"Neurology"},{"key":"B84","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s12974-016-0577-8","article-title":"Neuromyelitis optica study model based on chronic infusion of autoantibodies in rat cerebrospinal fluid","volume":"13","author":"Marignier","year":"2016","journal-title":"J Neuroinflamm"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M110.000877","article-title":"Quantitative proteomics and metabolomics analysis of normal human cerebrospinal fluid samples","volume":"9","author":"Stoop","year":"2010","journal-title":"Mol Cell Proteomics"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2024-226336","article-title":"Imaging mass cytometry-based characterization of fibroblast subsets and their cellular niches in systemic sclerosis","volume":"84","author":"Rius Rigau","year":"2024","journal-title":"Ann Rheumatic Dis"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01976-y","article-title":"DNA-barcoded signal amplification for imaging mass cytometry enables sensitive and highly multiplexed tissue imaging","volume":"20","author":"Hosogane","year":"2023","journal-title":"Nat Methods"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00556-8","article-title":"CODEX multiplexed tissue imaging with DNA-conjugated antibodies","volume":"16","author":"Black","year":"2021","journal-title":"Nat Protoc"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2017.07.001","article-title":"Endocrinology meets metabolomics: achievements, pitfalls, and challenges","volume":"28","author":"Tokarz","year":"2017","journal-title":"Trends Endocrinol Metab"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.70","article-title":"A guide to immunometabolism for immunologists","volume":"16","author":"O\u2019Neill","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B91","doi-asserted-by":"publisher","first-page":"103672","DOI":"10.1016\/j.msard.2022.103672","article-title":"Serum metabolic profiles and metal levels of patients with multiple sclerosis and patients with neuromyelitis optica spectrum disorders - NMR spectroscopy and ICP-MS studies","volume":"60","author":"Toczylowska","year":"2022","journal-title":"Mult Scler Relat Disord"},{"key":"B92","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12035-025-04923-4","article-title":"Multi-omics mendelian randomization reveals immunometabolic signatures of the gut microbiota in optic neuritis and the potential therapeutic role of vitamin B6","author":"Wang","year":"2025","journal-title":"Mol Neurobiol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.315","article-title":"Applications of multi-omics analysis in human diseases","volume":"4","author":"Chen","year":"2023","journal-title":"MedComm"},{"key":"B94","doi-asserted-by":"publisher","first-page":"107739","DOI":"10.1016\/j.biotechadv.2021.107739","article-title":"Using machine learning approaches for multi-omics data analysis: A review","volume":"49","author":"Reel","year":"2021","journal-title":"Biotechnol Adv"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.3389\/frai.2023.1098308","article-title":"Missing data in multi-omics integration: Recent advances through artificial intelligence","volume":"6","author":"Flores","year":"2023","journal-title":"Front Artif Intell"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1380386","article-title":"Unravelling B cell heterogeneity: insights into flow cytometry-gated B cells from single-cell multi-omics data","volume":"15","author":"Pernes","year":"2024","journal-title":"Front Immunol"},{"key":"B97","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.3390\/biomedicines12071496","article-title":"Navigating challenges and opportunities in multi-omics integration for personalized healthcare","volume":"12","author":"Mohr","year":"2024","journal-title":"Biomedicines"},{"key":"B98","doi-asserted-by":"publisher","first-page":"20170387","DOI":"10.1098\/rsif.2017.0387","article-title":"Opportunities and obstacles for deep learning in biology and medicine","volume":"15","author":"Ching","year":"2018","journal-title":"J R Soc Interface"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1027158","article-title":"Granzyme B in circulating CD8+ T cells as a biomarker of immunotherapy effectiveness and disability in neuromyelitis optica spectrum disorders","volume":"13","author":"Shi","year":"2022","journal-title":"Front Immunol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2019.01.047","article-title":"Foxp3+ regulatory T cells expression in neuromyelitis optica spectrum disorders","volume":"30","author":"Brill","year":"2019","journal-title":"Mult Scler Relat Disord"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02266-0","article-title":"Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder","volume":"18","author":"Ma","year":"2021","journal-title":"Journal Neuroinflamm"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.3109\/00207454.2016.1163550","article-title":"Th17 cells in neuromyelitis optica spectrum disorder: a review","volume":"126","author":"Lin","year":"2016","journal-title":"Int J Neurosci"},{"key":"B104","doi-asserted-by":"publisher","first-page":"3146","DOI":"10.1038\/s41598-024-53661-5","article-title":"Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders","volume":"14","author":"Nishiyama","year":"2024","journal-title":"Sci Rep"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.637829","article-title":"Role of the IL-23\/IL-17 pathway in rheumatic diseases: an overview","volume":"12","author":"Schinocca","year":"2021","journal-title":"Front Immunol"},{"key":"B106","doi-asserted-by":"publisher","first-page":"2856","DOI":"10.1038\/s41467-020-16625-7","article-title":"Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica","volume":"11","author":"Agasing","year":"2020","journal-title":"Nat Commun"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1800010","DOI":"10.1183\/13993003.00010-2018","article-title":"Reassessing Th1 versus Th17.1 in sarcoidosis: new tricks for old dogma","volume":"51","author":"Chen","year":"2018","journal-title":"Eur Respir J"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.004","article-title":"T follicular helper cell differentiation, function, and roles in disease","volume":"41","author":"Crotty","year":"2014","journal-title":"Immunity"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2020.1764352","article-title":"Moving beyond anti-aquaporin-4 antibodies: emerging biomarkers in the spectrum of neuromyelitis optica","volume":"20","author":"Rocca","year":"2020","journal-title":"Expert Rev Neurother"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200134","article-title":"Immune repertoire profiling reveals its clinical application potential and triggers for neuromyelitis optica spectrum disorders","volume":"10","author":"Miao","year":"2023","journal-title":"Neurol Neuroimmunology Neuroinflamm"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000001070","article-title":"B-cell compartmental features and molecular basis for therapy in autoimmune disease","volume":"8","author":"Zhang","year":"2021","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1080\/25785826.2024.2334002","article-title":"Establishment of novel cell lines that maintain the features of B cells derived from patients with neuromyelitis optica spectrum disorder","volume":"47","author":"Sano","year":"2024","journal-title":"Immunol Med"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf086","article-title":"CD21lo B cell subsets are recruited to the central nervous system in acute neuromyelitis optica","volume":"148","author":"Nishigori","year":"2025","journal-title":"Brain"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.02.020","article-title":"Distinct dynamics of antigen-specific induction and differentiation of different CD11c(+)Tbet(+) B-cell subsets","volume":"152","author":"Steuten","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2017.05.008","article-title":"Role of CD11c(+) T-bet(+) B cells in human health and disease","volume":"321","author":"Karnell","year":"2017","journal-title":"Cell Immunol"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31817-3","article-title":"Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomized placebo-controlled phase 2\/3 trial","volume":"394","author":"Cree","year":"2019","journal-title":"Lancet"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-016-8188-y","article-title":"Rituximab in the treatment of Neuromyelitis optica: a multicenter Italian observational study","volume":"263","author":"Annovazzi","year":"2016","journal-title":"J Neurol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200173","article-title":"Long-term effects of IL-6 receptor blockade therapy on regulatory lymphocytes and neutrophils in neuromyelitis optica spectrum disorder","volume":"11","author":"Matsuoka","year":"2024","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.227298","article-title":"Binding affinity and specificity of neuromyelitis optica autoantibodies to aquaporin-4 M1\/M23 isoforms and orthogonal arrays","volume":"286","author":"Crane","year":"2011","journal-title":"J Biol Chem"},{"key":"B120","doi-asserted-by":"publisher","first-page":"e1034","DOI":"10.1212\/NXI.0000000000001034","article-title":"Molecular level characterization of circulating aquaporin-4 antibodies in neuromyelitis optica spectrum disorder","volume":"8","author":"Li","year":"2021","journal-title":"Neurology-Neuroimmunology Neuroinflamm"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053019","article-title":"Unraveling the complex interplay between T cell metabolism and function","volume":"36","author":"Geltink","year":"2018","journal-title":"Annu Rev Immunol"},{"key":"B122","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1016\/bs.adgen.2015.11.004","article-title":"Integrative analysis of multi-omics data for discovery and functional studies of complex human diseases","volume":"93","author":"Sun","year":"2016","journal-title":"Adv Genet"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008160","article-title":"Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD","volume":"93","author":"Watanabe","year":"2019","journal-title":"Neurology"},{"key":"B126","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s12974-021-02138-7","article-title":"Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder","volume":"18","author":"Schindler","year":"2021","journal-title":"J Neuroinflamm"},{"key":"B127","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1186\/s12974-019-1594-1","article-title":"The history of neuromyelitis optica. Part 2: \u2018Spinal amaurosis\u2019, or how it all began","volume":"16","author":"Jarius","year":"2019","journal-title":"J Neuroinflamm"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.9783-22","article-title":"Paraneoplastic neuromyelitis optica spectrum disorder related to glucose-regulated protein 78 (GRP78) autoantibodies in a patient with lynch syndrome-associated colorectal cancer","volume":"62","author":"Minomo","year":"2023","journal-title":"Intern Med"},{"key":"B129","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nrneurol.2014.141","article-title":"Treatment of neuromyelitis optica: state-of-the-art and emerging therapies","volume":"10","author":"Papadopoulos","year":"2014","journal-title":"Nat Rev Neurol"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2025.1555380","article-title":"Multimodal AI diagnostic system for neuromyelitis optica based on ultrawide-field fundus photography","volume":"12","author":"Gu","year":"2025","journal-title":"Front Med (Lausanne)"},{"key":"B131","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/s12672-025-01836-5","article-title":"Machine learning-assisted cancer diagnosis in patients with paraneoplastic autoantibodies","volume":"16","author":"Maleki","year":"2025","journal-title":"Discov Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1665688\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T05:34:16Z","timestamp":1756791256000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1665688\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,2]]},"references-count":131,"alternative-id":["10.3389\/fimmu.2025.1665688"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1665688","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,2]]},"article-number":"1665688"}}