Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens

Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, we assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Our findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.

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Publication Details

Journal
Acta Neuropathologica
Published
2025-04-25
DOI
https://doi.org/10.1007/s00401-025-02882-7
Citations
4
Primary Topic
Autoimmune Neurological Disorders and Treatments
Type
article
Field-Weighted Citation Impact
5.56

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article

Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens

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4 citations
Acta Neuropathologica
Autoimmune Neurological Disorders and Treatments
5.56
article

Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens

Bogdan Draganski, Virginie Desestret, Dennis W. Dickson, Jean‐Philippe Brouland, Giovanni Di Liberto, Ingrid Wagner, Verena Endmayr, Marco Prinz, Divyanshu Dubey, Jasmin Rahimi, Ilena Vincenti, Alex Vicino, Alberto Vogrig, Sarosh R. Irani, Karoline Ostertag, Kristóf Égervári, Jérôme Honnorat, Laura Parkkinen, Mario Kreutzfeldt, Shanu F. Roemer, Marianna Spatola, Stephan Frank, Laurence de Leval, Margot Piccinno, Doron Merkler, Romana Höftberger, Renaud Du Pasquier, Anne‐Katrin Pröbstel, Ekkehard Hewer, David Meyronet, Sean J Pittock
article en
4 citations

Abstract

Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, we assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Our findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.

Acta NeuropathologicaVol. 149(1)
Université Claude Bernard Lyon 1 (FR), University of Geneva (CH), University of Bern (CH), University of Udine (IT), Centre National de la Recherche Scientifique (FR), Mayo Clinic (US), Inserm (FR), University of Freiburg (DE), University of Basel (CH), University Hospital Bonn (DE), University Hospital of Bern (CH), German Center for Neurodegenerative Diseases (DE), University Hospital of Basel (CH), John Radcliffe Hospital (GB), Donauspital (AT), University of Oxford (GB), Klinik Hietzing (AT), Azienda Unità Sanitaria Locale di Ferrara (IT), Hospices Civils de Lyon (FR), University Hospital of Geneva (CH), Centre de Recherche en Cancérologie de Lyon (FR), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Universitat de Barcelona (ES), Medical University of Vienna (AT), University of Lausanne (CH)
Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Université de Genève, Fondation Pierre Mercier pour la Science, European Research Council
Good health and well-being
Openalex Percentile: Top 4%
Autoimmune Neurological Disorders and Treatments
5.56
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