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Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8<jats:sup>+<\/jats:sup>\/perforin<jats:sup>+<\/jats:sup>\/granzyme A\/B<jats:sup>+<\/jats:sup> cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.<\/jats:p><jats:p>Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.<\/jats:p>","DOI":"10.1007\/s00401-023-02678-7","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T19:02:53Z","timestamp":1706986973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis"],"prefix":"10.1007","volume":"147","author":[{"given":"Yong","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Endmayr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Zekeridou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"McKeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Leypoldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Hess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicja","family":"Kalinowska-Lyszczarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Klang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akos","family":"Pakozdy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"H\u00f6ftberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Hametner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Haider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9sir\u00e9e","family":"De Simoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f6nke","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Gelpi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"R\u00f6cken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Oberndorfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Lassmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia F.","family":"Lucchinetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5769-1100","authenticated-orcid":false,"given":"Romana","family":"H\u00f6ftberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"2678_CR1","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/s41586-021-03892-7","volume":"597","author":"M Absinta","year":"2021","unstructured":"Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD, Jin J et al (2021) A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. 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Lucchinetti report no relevant disclosures. Anastasia Zekeridou reports consultation for Alexion Pharmaceuticals with no personal compensation, has research funding from Roche not relevant to this work and has patents pending for Tenascin-R-IgG, PDE10A-IgG and DACH1-IgG as biomarkers of neurological autoimmunity. Frank Leypoldt is supported by German Ministry of Education and Research (01GM1908A and 01GM2208), E-Rare Joint Transnational research support (ERA-Net, LE3064\/2\u20131), Stiftung Pathobiochemie of the German Society for Laboratory Medicine and HORIZON MSCA 2022 Doctoral Network 101119457 \u2014 IgG4-TREAT and discloses speaker honoraria from Grifols, Teva, Biogen, Bayer, Roche, Novartis, Fresenius, travel funding from Merck, Grifols and Bayer and serving on advisory boards for Roche, Biogen and Alexion. Alicja Kalinowska-Lyszczarz received grant funding from Novartis and received compensation for speaking and consulting services from Biogen, Bayer, Novartis, Roche, Merck, Teva, CSL Behring, Shire, Janssen, Bristol-Myers Squibb, and Sanofi-Genzyme. None of the consulting agreements are relevant to the submitted work. Romana H\u00f6ftberger reports honoraria from Novartis and Biogen. The Medical University of Vienna (Austria; employer of Prof. H\u00f6ftberger) receives payment for antibody assays and for antibody validation experiments organized by Euroimmun (L\u00fcbeck, Germany).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"31"}}