Forkhead box versus NF-κB hippocampal snRNA-seq profiles distinguish anti-Drebrin- and anti-GAD65-positive encephalitis.

Overview

1. Department of Epileptology, Neurology, RWTH Aachen University,Aachen, Germany
2. Department of Epileptology, University Hospital Bonn,Venusberg-Campus 1, Bonn, D-53127 Germany
3. Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna,Vienna, Austria
4. Department of Neuroradiology, University Hospital Bonn,Bonn, Germany
5. i-Synapse, Cairns, Australia
6. Clinic for Neurosurgery, University Hospital Bonn,Bonn, Germany
7. Institute of Cellular Neurosciences II, University Hospital Bonn,Bonn, Germany

Abstract

Background and objectives: Autoantibodies (ABs) against intracellular proteins, including glutamate-decarboxylase 65 (anti-GAD65), are increasingly recognized in autoimmune and limbic encephalitis (AE/LE). Anti-GAD65 LE frequently progresses to severe temporal lobe epilepsy (TLE), neuropathologically characterized by hippocampal sclerosis (HS) and variable infiltration of cytotoxic T lymphocytes (CTLs). Recently, we have identified Drebrin (DBN) as a new intracellular target protein of ABs in index patients with suspected AE. Here, we aim to characterize key molecular and cellular signatures of hippocampal tissue from anti-GAD65- (GAD65-TLE) versus anti-DBN-positive TLE (DBN-TLE) patients correlated to clinical parameters.

Methods: We examined hippocampal neuropathology and performed exploratory single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue from DBN- and GAD65-TLE patients, integrated with key clinical data from a large patient cohort.

Results: Although the hippocampi of the two patient groups were neuropathologically virtually indistinguishable, exploratory snRNA-seq revealed distinct transcriptional programs. DBN-TLE patients (n = 2) showed transcriptional signatures enriched for forkhead box (Fox) transcription factor family, whereas GAD65-TLE patients (n = 2) displayed transcriptional signatures enriched for transcripts related to NF-κB- signaling. In a larger cohort, DBN-TLE patients (n = 22) showed significantly more favorable pharmacological responsiveness than GAD65-TLE patients (n = 35), who were largely pharmacoresistant. Notably, in a T cell-mediated mouse model for LE, similar inflammatory programs were dynamically regulated.

Conclusion: These findings provide a discovery-based transcriptomic signatures of rare autoimmune hippocampal tissue, revealing distinct immune-associated transcriptional states in anti-DBN- versus anti-GAD65-positive AE/TLE patients despite virtually indistinguishable hippocampal pathology in both groups and support further investigations of disease-specific therapeutic strategies.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-026-03951-8.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:32931082, at figshare; found in DataCite
• figshare:32931085, at figshare; found in DataCite
• figshare:32931088, at figshare; found in DataCite

Data availability

The RNA-seq datasets generated and analyzed during this study are available in the Gene Expression Omnibus (GEO) repository under the accession numbers **GSE303810** (Human snRNA-seq dataset) and **GSE303749** (Mouse RNA-seq dataset). To facilitate peer review while the records remain private, the following secure tokens have been generated: - For **GSE303810** : mzsragswzvexlqv - For **GSE303749** : anobckyqptwvdmz

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 5 keywords, 16 MeSH terms, 1 funder, 56 references.

Cite

This paper

van Loo, K. M., Galvis-Montes, D. S., Breuer, A., Berns, J. L., Hummel, C. A., Baumgartner, T., Freyberg, M., Mair, K. M., Bauer, J., Rüber, T., van Waardenberg, A. J., Hamed, M., Borger, V., Vatter, H., Surges, R., Schoch, S., Becker, A. J., & Pitsch, J. (2026). Forkhead box versus NF-κB hippocampal snRNA-seq profiles distinguish anti-Drebrin- and anti-GAD65-positive encephalitis. Journal of neuroinflammation, 23(1), 232. https://doi.org/10.1186/s12974-026-03951-8

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