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Abstract Details

Neuronal pSTAT1 Hallmarks Synaptic Pathology in Autoimmune Encephalitis Against Intracellular Antigens
Autoimmune Neurology
S18 - Paraneoplastic Neurological Disorders, irAE, Stiff Person, IGLON5 (1:24 PM-1:36 PM)
003
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.

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.

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.

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.

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.

Authors/Disclosures
Giovanni Di Liberto, MD, PhD
PRESENTER
Dr. Di Liberto has nothing to disclose.
Kristof Egervari, MD, PhD Dr. Egervari has nothing to disclose.
Alberto Vogrig, MD, PhD (University of Udine) Alberto Vogrig has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Eisai. Alberto Vogrig has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Angelini. The institution of Alberto Vogrig has received research support from Ministero della Salute, Bando Ricerca Finalizzata.
Marianna Spatola, MD, PhD (FUNDACIÓ DE RECERCA BIOMEDICA CLÍNIC IDIBAPS) The institution of Dr. Spatola has received research support from Spanish National Health Institute (Carlos III), FIS grant. The institution of Dr. Spatola has received research support from Spanish National Institute of Health - Miguel Servet Grant. The institution of Dr. Spatola has received research support from La Caixa Foundation.
Margot Piccinno, Jr., Doctoral Student Mrs. Piccinno has nothing to disclose.
Ilena Vincenti, PhD Dr. Vincenti has nothing to disclose.
ingrid wagner, technician Mrs. wagner has nothing to disclose.
Mario Kreutzfeldt, PhD Dr. Kreutzfeldt has nothing to disclose.
Verena Endmayr, PhD Dr. Endmayr has nothing to disclose.
Karoline D. Ostertag, MD Dr. Ostertag has nothing to disclose.
Jasmin Rahimi (Wiener Gesundheitsverbund, Klinik Donaustadt) Dr. Rahimi has nothing to disclose.
Alex Vicino (Department of Clinical Neurosciences, Neurology Service, Lausanne University Hospital and University of Lausanne, Switzerland) No disclosure on file
Anne-Katrin Proebstel, MD (University Hospital Basel) The institution of Dr. Proebstel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Proebstel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. The institution of Dr. Proebstel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Proebstel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. The institution of Dr. Proebstel has received research support from Biogen. Dr. Proebstel has received intellectual property interests from a discovery or technology relating to health care.
David Meyronet No disclosure on file
Stephan Frank, MD Prof. Frank has nothing to disclose.
Marco Prinz, MD Prof. Prinz has nothing to disclose.
Ekkehard Hewer, MD Prof. Hewer has nothing to disclose.
Jean-Philippe Brouland (Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland) No disclosure on file
Laura Parkkinen, PhD The institution of Prof. Parkkinen has received research support from GSK. The institution of Prof. Parkkinen has received research support from NIH. The institution of Prof. Parkkinen has received research support from NIHR Oxford Biomedical Research Centre.
Bogdan Draganski, MD Prof. Draganski has nothing to disclose.
Virginie Desestret Virginie Desestret has nothing to disclose.
Divyanshu Dubey, MD, FAAN (Mayo Clinic) The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received research support from UCB. Dr. Dubey has received research support from David J. Tomassoni ALS Research Grant Program . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care.
Sean J. Pittock, MD, FAAN (Mayo Clinic Dept of Neurology) Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys Therapeutics. The institution of Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arialys. The institution of Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. The institution of Dr. Pittock has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion/AstraZeneka. The institution of Dr. Pittock has received research support from NIH. The institution of Dr. Pittock has received research support from Alexion/AstraZeneka. The institution of Dr. Pittock has received research support from F. Hoffman/LaRoche/Genentech. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Dr. Pittock has received publishing royalties from a publication relating to health care.
Shanu Roemer Shanu Roemer has nothing to disclose.
Dennis W. Dickson, MD (Mayo Clinic) Dr. Dickson has nothing to disclose.
Romana Hoeftberger (Medical University of Vienna) Romana Hoeftberger has received personal compensation in the range of $500-$4,999 for serving as a speaker with Euroimmun and UCB Biopharma.
Sarosh R. Irani, MD, PhD, FRCP, FEAN (Mayo Clinic) Dr. Irani has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for UCB, Immunovant, MedImmun, Roche, Janssen, Cerebral therapeutics, Biogen, Amgen, Argenex, Clarivate, IQVIA, BioHaven therapeutics, ADC therapeutics, Brain, CSL Behring, and ONO Pharma.. Dr. Irani has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Irani has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Irani has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Brain. Dr. Irani has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for LLPs. Dr. Irani has received intellectual property interests from a discovery or technology relating to health care. Dr. Irani has received intellectual property interests from a discovery or technology relating to health care. Dr. Irani has received intellectual property interests from a discovery or technology relating to health care.
Jerome Honnorat, MD, PhD (Hospices Civils de Lyon) The institution of Jerome Honnorat, MD, PhD has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for journal of neurology.
Renaud A. Du Pasquier, MD, FAAN (Service of neurology, CHUV) Dr. Du Pasquier has nothing to disclose.
Doron Merkler, MD Prof. Merkler has nothing to disclose.