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

Guo Yong; Verena Endmayr; Anastasia Zekeridou; Andrew McKeon; Frank Leypoldt; Katharina Hess; Alicja Kalinowska‑Lyszczarz; Andrea Klang; Akos Pakozdy; Elisabeth Höftberger; Simon Hametner; Carmen Haider; Désirée De Simoni; Sönke Peters; Ellen Gelpi; Christoph Röcken; Stefan Oberndorfer; Hans Lassmann; Claudia F. Lucchinetti; Romana Höftberger

doi:10.1007/s00401-023-02678-7

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Title (eng)

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

Author

Guo Yong

Verena Endmayr

Anastasia Zekeridou

Andrew McKeon

Frank Leypoldt

Katharina Hess

Alicja Kalinowska‑Lyszczarz

Andrea Klang

University of Veterinary Medicine Vienna

Akos Pakozdy

University of Veterinary Medicine Vienna

Elisabeth Höftberger

Simon Hametner

Carmen Haider

Désirée De Simoni

Sönke Peters

Ellen Gelpi

Christoph Röcken

Stefan Oberndorfer

Hans Lassmann

Claudia F. Lucchinetti

Romana Höftberger

Abstract (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.

Keywords (eng)

HumansAnimalsDogsGlial Fibrillary Acidic Protein metabolismEncephalomyelitis PathologyAstrocytes OathologyAutoimmune Diseases of the Nervous System Cerebrospinal FluidAutoimmune Diseases of the Nervous Systemce TherapyMeningoencephalitis Cerebrospinal FluidMeningoencephalitis PathologyAutoantibodies

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4244

DOI

10.1007/s00401-023-02678-7

Is in series

Title (eng)

Acta Neuropathologica

Volume