2025 American Academy of Neurology Abstract Website

Giovanni Di Liberto¹, Kristof Egervari², Alberto Vogrig³, Marianna Spatola⁴, Margot Piccinno⁵, Ilena Vincenti², Ingrid Wagner⁵, Mario Kreutzfeldt², Verena Endmayr⁶, Karoline Ostertag⁷, Jasmin Rahimi⁸, Alex Vicino⁹, Anne-Katrin Proebstel¹⁰, David Meyronet¹¹, Stephan Frank¹², Marco Prinz¹³, Ekkehard Hewer¹⁴, Jean-Philippe Brouland¹⁴, Laura Parkkinen¹⁵, Bogdan Draganski¹⁶, Virginie Desestret¹⁷, Divyanshu Dubey¹⁸, Sean Pittock¹⁸, Shanu Roemer¹⁹, Dennis Dickson¹⁹, Romana Hoeftberger⁶, Sarosh Irani²⁰, Jerome Honnorat¹⁷, Renaud Du Pasquier⁹, Doron Merkler²
¹Department of Clinical Neurosciences, Neurology Service, Lausanne University Hospital and University of Lausanne, Switzerland & Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland, ²Department of Pathology and Immunology, University of Geneva & Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland, ³Department of Medicine (DMED), University of Udine & Clinical Neurology, Department of Head-Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy, ⁴Neuroimmunology Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clinic, University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain, ⁵Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland, ⁶Division of Neuropathology and Neurochemistry, Department of Neurology & Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria, ⁷Department of Neurology, Clinic Hietzing, Vienna, Austria, ⁸Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders Klinik Donaustadt, Vienna, Austria, ⁹Department of Clinical Neurosciences, Neurology Service, Lausanne University Hospital and University of Lausanne, Switzerland, ¹⁰Department of Neurology and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) & Departments of Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland, ¹¹Institute of Neuropathology, Hospices Civils de Lyon, F-69008 & Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, CEDEX 08, F-69373 & Université de Lyon, Université Claude Bernard Lyon 1, CEDEX 08, F-69373, Lyon, France, ¹²Department of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland, ¹³Institute of Neuropathology, University of Freiburg, Freiburg, Germany & Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany, ¹⁴Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, ¹⁵Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK, ¹⁶Universitätsklinik für Neurologie, Inselspital, University of Bern, Bern, Switzerland, ¹⁷French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MeLiS – UCBL – CNRS UMR 5284 – INSERM U1314, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France, ¹⁸Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota & Center for Multiple Sclerosis and Autoimmune Neurology, Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA, ¹⁹Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA, ²⁰Autoimmune Neurology Group, West Wing, Level 3, John Radcliffe Hospital, University of Oxford, Oxford, UK & Departments of Neurology and Neuroscience, Mayo Clinic, Jacksonville, Florida, USA

Objective:

To compare the histopathological features of autoimmune encephalitis (AE) subtypes targeting intracellular (IC-AE) versus neural surface antigens (NS-AE) and identify potential biomarkers and mechanisms for targeted therapeutic interventions.

Background:

Autoimmune encephalitis is a neuroinflammatory disorder caused by immune responses against neural autoantigens. IC-AE, driven by T-cell-mediated mechanisms, often leads to severe neurodegeneration and poor outcomes, while NS-AE is associated with a better prognosis and milder neurodegeneration. Understanding the cellular and molecular distinctions between these AE subtypes is essential for developing targeted therapies.

Design/Methods:

Brain tissue samples from NS-AE (n=7) and IC-AE (n=12) patients were analyzed. Immunofluorescence staining was performed to evaluate neuronal pSTAT1 expression, the presence of CD8+ tissue-resident memory (TRM) T cells, synaptic engulfment by GPNMB+ phagocytes, and complement C3 deposition on synapses. Differences in phagocyte activity and immune cell infiltration were examined across subtypes.

Results:

Neuronal pSTAT1 expression was detected in 100% of IC-AE cases but was rare in NS-AE (14%). IC-AE exhibited abundant CD8+ TRM cells (84.4 ± 33.2 cells/mm²) compared to NS-AE (6.9 ± 2.4 cells/mm²) and non-neurological controls (1.5 ± 0.3 cells/mm²), suggesting a compartmentalized immune response. GPNMB+ phagocytes in IC-AE displayed increased synaptic engulfment without complement C3 deposition, indicating a complement-independent mechanism. In contrast, NS-AE showed prominent complement C3 deposition on synapses, particularly in NMDAR-ab-AE, with significantly more C3-tagged synapses and higher levels of complement-mediated synaptic engulfment by CNS phagocytes.

Conclusions:

IC-AE is marked by neuronal pSTAT1 signaling, CD8+ TRM infiltration, and complement-independent synaptic loss, while NS-AE involves complement-mediated synaptic pathology. Neuronal pSTAT1 could serve as a biomarker and therapeutic target in T-cell-driven encephalitis, particularly IC-AE, suggesting different therapeutic strategies for each AE subtype.