New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis

• Published in: Acta neuropathologica Vol. 147; no. 1; p. 31
• Main Authors: Guo, Yong, Endmayr, Verena, Zekeridou, Anastasia, McKeon, Andrew, Leypoldt, Frank, Hess, Katharina, Kalinowska-Lyszczarz, Alicja, Klang, Andrea, Pakozdy, Akos, Höftberger, Elisabeth, Hametner, Simon, Haider, Carmen, De Simoni, Désirée, Peters, Sönke, Gelpi, Ellen, Röcken, Christoph, Oberndorfer, Stefan, Lassmann, Hans, Lucchinetti, Claudia F., Höftberger, Romana
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2024; Springer Nature B.V
• Subjects: Animals; Aquaporin 4; Astrocytes; Astrocytes - pathology; Autoantibodies; Autoimmune Diseases of the Nervous System - cerebrospinal fluid; Autoimmune Diseases of the Nervous System - therapy; Autoimmunity; Autopsies; Autopsy; Biopsy; CD8 antigen; Central nervous system; Cerebrospinal fluid; Complement component C4; Cytotoxicity; Dogs; Encephalitis; Encephalomyelitis - pathology; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - metabolism; Humans; Immunological memory; Immunoreactivity; Inflammation; Lymphocytes T; Major histocompatibility complex; Medicine; Medicine & Public Health; Memory cells; Meningoencephalitis; Meningoencephalitis - cerebrospinal fluid; Meningoencephalitis - pathology; Neuronal-glial interactions; Neurosciences; Original Paper; Pathology; Perforin; Phenotypes; Regeneration; Autoimmunity; Biopsies; Autopsies; Magnetic resonance imaging; GFAP
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-023-02678-7

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.