Cerebrospinal fluid proteomics indicates immune dysregulation and neuronal dysfunction in antibody associated autoimmune encephalitis

Saskia Räuber, Christina B. Schroeter, Christine Strippel, Christopher Nelke, Tillmann Ruland, Andre Dik, Kristin S. Golombeck, Liesa Regner-Nelke, Manuela Paunovic, Daniela Esser, Christian Münch, Felix Rosenow, Martijn van Duijn, Antonia Henes, Tobias Ruck, Ido Amit, Frank Leypoldt, Maarten J. Titulaer, Heinz Wiendl, Sven G. MeuthGerd Meyer zu Hörste, Nico Melzer*

*Corresponding author for this work

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Abstract

Autoimmune Encephalitis (AE) spans a group of non-infectious inflammatory conditions of the central nervous system due to an imbalanced immune response. Aiming to elucidate the pathophysiological mechanisms of AE, we applied an unsupervised proteomic approach to analyze the cerebrospinal fluid (CSF) protein profile of AE patients with autoantibodies against N-methyl-D-aspartate receptor (NMDAR) (n = 9), leucine-rich glioma-inactivated protein 1 (LGI1) (n = 9), or glutamate decarboxylase 65 (GAD65) (n = 8) compared to 9 patients with relapsing-remitting multiple sclerosis as inflammatory controls, and 10 patients with somatic symptom disorder as non-inflammatory controls. We found a dysregulation of the complement system, a disbalance between pro-inflammatory and anti-inflammatory proteins on the one hand, and dysregulation of proteins involved in synaptic transmission, synaptogenesis, brain connectivity, and neurodegeneration on the other hand to a different extent in all AE subtypes compared to non-inflammatory controls. Furthermore, elevated levels of several proteases and reduction in protease inhibitors could be detected in all AE subtypes compared to non-inflammatory controls. Moreover, the different AE subtypes showed distinct protein profiles compared to each other and inflammatory controls which may facilitate future identification of disease-specific biomarkers. Overall, CSF proteomics provides insights into the complex pathophysiological mechanisms of AE, including immune dysregulation, neuronal dysfunction, neurodegeneration, and altered protease function.

Original languageEnglish
Article number102985
JournalJournal of Autoimmunity
Volume135
DOIs
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
This project was supported by the German Reuter Foundation ( ERARE18-202 UltraAIE) under the frame of E-Rare-3, the ERA-Net for Research on Rare Diseases, and the German Federal Ministry of Education and Research (Comprehensive, Orchestrated, National Network to 603 Explain, Categorize and Treat autoimmune encephalitis and allied diseases within the German 604 NEtwork for Research on AuToimmune Encephalitis – CONNECT GENERATE; 01GM1908). GMzH was further supported by grants from the German Research Foundation ( ME4050/12–1 , ME4050/13–1 , ME4050/8–1 ).

Publisher Copyright: © 2022 The Author(s)

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