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In a subset of cases, no autoantibodies are detectable with the currently used routine assays. This study aimed to determine whether the levels of expression of aquaporin\u20104 (AQP4), excitatory amino acid transporter 2 (EAAT2), or complement C3\/C3d and C5b\u20109 in human astrocytes following incubation with patient sera under inflammatory conditions differ between the various NMOSD subtypes and whether such differences can help to identify autoantibody\u2010mediated cases of NMOSD. Levels of AQP4, EAAT2, complement C3\/C3d and C5b\u20109 epitope expression on human astrocytes pretreated with various cytokines were quantitatively analyzed via indirect immunofluorescence after exposure to sera from patients with AQP4\u2010IgG seropositive, MOG\u2010IgG seropositive, and AQP4\/MOG\u2010IgG double seronegative NMOSD. Significant differences in AQP4 and C3d epitope expression were observed, with IL\u201017A, IL\u201010, and IL\u20106 pre\u2010treatment notably influencing astrocytic responses. Using uniform manifold approximation and projection (UMAP), patients were classified into clusters corresponding to AQP4\u2010IgG seropositive, MOG\u2010IgG seropositive, or double seronegative NMOSD. These results demonstrate distinct astrocytic staining patterns across NMOSD subtypes, providing a potential diagnostic tool for distinguishing between autoantibody\u2010mediated astrocytopathy and other cases. These findings suggest specific pathogenic mechanisms linked to each NMOSD subtype, which may have implications for tailoring therapeutic strategies based on cytokine involvement and astrocyte reactivity.<\/jats:p>","DOI":"10.1002\/glia.24675","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T11:29:52Z","timestamp":1737977392000},"page":"1090-1106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Distinguishing Neuromyelitis Optica Spectrum Disorders Subtypes: A Study on\n                    <scp>AQP4<\/scp>\n                    and C3d Epitope Expression in Cytokine\u2010Primed Human Astrocytes"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8316-6193","authenticated-orcid":false,"given":"Marlen","family":"Alisch","sequence":"first","affiliation":[{"name":"Experimental and Clinical Research Center, Max\u2010Delbr\u00fcck\u2010Center for 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