PMID- 38310187 OWN - NLM STAT- MEDLINE DCOM- 20240205 LR - 20240223 IS - 1432-0533 (Electronic) IS - 0001-6322 (Print) IS - 0001-6322 (Linking) VI - 147 IP - 1 DP - 2024 Feb 3 TI - New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis. PG - 31 LID - 10.1007/s00401-023-02678-7 [doi] LID - 31 AB - Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. 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(+)/perforin(+)/granzyme A/B(+) 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.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. CI - (c) 2024. The Author(s). FAU - Guo, Yong AU - Guo Y AD - Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA. FAU - Endmayr, Verena AU - Endmayr V AD - Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. AD - Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - Zekeridou, Anastasia AU - Zekeridou A AD - Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA. AD - Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA. FAU - McKeon, Andrew AU - McKeon A AD - Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA. AD - Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA. FAU - Leypoldt, Frank AU - Leypoldt F AD - Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Kiel, Lubeck, Germany. AD - Department of Neurology, University Medical Center Schleswig-Holstein and Kiel University, Kiel, Germany. FAU - Hess, Katharina AU - Hess K AD - Institute of Neuropathology, University Hospital Muenster, Muenster, North Rhine Westphalia, Germany. AD - Department of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Kalinowska-Lyszczarz, Alicja AU - Kalinowska-Lyszczarz A AD - Department of Neurology, Division of Neurochemistry and Neuropathology, Poznan University of Medical Sciences, Poznan, Poland. FAU - Klang, Andrea AU - Klang A AD - Institute of Pathology, University of Veterinary Medicine, Vienna, Austria. FAU - Pakozdy, Akos AU - Pakozdy A AD - Internal Medicine, University Clinic for Small Animals, University of Veterinary Medicine, Vienna, Austria. FAU - Hoftberger, Elisabeth AU - Hoftberger E AD - Internal Medicine, University Clinic for Small Animals, University of Veterinary Medicine, Vienna, Austria. FAU - Hametner, Simon AU - Hametner S AD - Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. AD - Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - Haider, Carmen AU - Haider C AD - Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. AD - Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - De Simoni, Desiree AU - De Simoni D AD - Division of Neurology, Karl Landsteiner University of Health Sciences, University Hospital, St. Polten, Austria. FAU - Peters, Sonke AU - Peters S AD - Clinic for Radiology and Neuroradiology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany. FAU - Gelpi, Ellen AU - Gelpi E AD - Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. AD - Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - Rocken, Christoph AU - Rocken C AD - Department of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Oberndorfer, Stefan AU - Oberndorfer S AD - Division of Neurology, Karl Landsteiner University of Health Sciences, University Hospital, St. Polten, Austria. FAU - Lassmann, Hans AU - Lassmann H AD - Center for Brain Research, Medical University of Vienna, Vienna, Austria. FAU - Lucchinetti, Claudia F AU - Lucchinetti CF AD - Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA. clucchinetti@mayo.edu. FAU - Hoftberger, Romana AU - Hoftberger R AUID- ORCID: 0000-0002-5769-1100 AD - Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. romana.hoeftberger@meduniwien.ac.at. AD - Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. romana.hoeftberger@meduniwien.ac.at. LA - eng GR - R01 NS126227/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20240203 PL - Germany TA - Acta Neuropathol JT - Acta neuropathologica JID - 0412041 RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Autoantibodies) SB - IM MH - Humans MH - Animals MH - Dogs MH - Glial Fibrillary Acidic Protein/metabolism MH - *Encephalomyelitis/pathology MH - Astrocytes/pathology MH - *Autoimmune Diseases of the Nervous System/cerebrospinal fluid/therapy MH - *Meningoencephalitis/cerebrospinal fluid/pathology MH - Autoantibodies PMC - PMC10838242 OTO - NOTNLM OT - Autoimmunity OT - Autopsies OT - Biopsies OT - GFAP OT - Magnetic resonance imaging COIS- Yong Guo, Verena Endmayr, Andrew McKeon, Katharina Hess, Andrea Klang, Akos Pakozdy, Elisabeth Hoftberger, Simon Hametner, Carmen Haider, Desiree De Simoni, Sonke Peters, Ellen Gelpi, Christoph Rocken, Stefan Oberndorfer, Hans Lassmann, Claudia F. 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, LE3064/2-1), Stiftung Pathobiochemie of the German Society for Laboratory Medicine and HORIZON MSCA 2022 Doctoral Network 101119457 - 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 Hoftberger reports honoraria from Novartis and Biogen. The Medical University of Vienna (Austria; employer of Prof. Hoftberger) receives payment for antibody assays and for antibody validation experiments organized by Euroimmun (Lubeck, Germany). EDAT- 2024/02/04 00:42 MHDA- 2024/02/05 06:42 PMCR- 2024/02/03 CRDT- 2024/02/03 23:19 PHST- 2023/09/05 00:00 [received] PHST- 2023/12/24 00:00 [accepted] PHST- 2023/12/06 00:00 [revised] PHST- 2024/02/05 06:42 [medline] PHST- 2024/02/04 00:42 [pubmed] PHST- 2024/02/03 23:19 [entrez] PHST- 2024/02/03 00:00 [pmc-release] AID - 10.1007/s00401-023-02678-7 [pii] AID - 2678 [pii] AID - 10.1007/s00401-023-02678-7 [doi] PST - epublish SO - Acta Neuropathol. 2024 Feb 3;147(1):31. doi: 10.1007/s00401-023-02678-7.