https://phaidra.vetmeduni.ac.at/o:4244 New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis Yong, Guo Guo Yong Endmayr, Verena Verena Endmayr Zekeridou, Anastasia Anastasia Zekeridou McKeon, Andrew Andrew McKeon Leypoldt, Frank Frank Leypoldt Hess, Katharina Katharina Hess Kalinowska‑Lyszczarz, Alicja Alicja Kalinowska‑Lyszczarz Klang, Andrea Andrea Klang 0000-0001-5352-5757 University of Veterinary Medicine Vienna Pakozdy, Akos Akos Pakozdy 0000-0001-9816-6970 University of Veterinary Medicine Vienna Höftberger, Elisabeth Elisabeth Höftberger Hametner, Simon Simon Hametner Haider, Carmen Carmen Haider De Simoni, Désirée Désirée De Simoni Peters, Sönke Sönke Peters Gelpi, Ellen Ellen Gelpi Röcken, Christoph Christoph Röcken Oberndorfer, Stefan Stefan Oberndorfer Lassmann, Hans Hans Lassmann Lucchinetti, Claudia F. Claudia F. Lucchinetti Höftberger, Romana Romana Höftberger Springer journal article open access eng 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. Humans Animals Dogs Glial Fibrillary Acidic Protein metabolism Encephalomyelitis Pathology Astrocytes Oathology Autoimmune Diseases of the Nervous System Cerebrospinal Fluid Autoimmune Diseases of the Nervous Systemce Therapy Meningoencephalitis Cerebrospinal Fluid Meningoencephalitis Pathology Autoantibodies http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4244/download 10.1007/s00401-023-02678-7 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Acta Neuropathologica issn:0001-6322 VoR Acta Neuropathologica 147 1 6.67 MB 2024