Forkhead box versus NF-κB hippocampal snRNA-seq profiles distinguish anti-Drebrin- and anti-GAD65-positive encephalitis.
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.
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.
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.
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.
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.
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.
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.
Authors
van Loo van Loo, Galvis-Montes Galvis-Montes, Breuer Breuer, Berns Berns, Hummel Hummel, Baumgartner Baumgartner, Freyberg Freyberg, Mair Mair, Bauer Bauer, Rüber Rüber, van Waardenberg van Waardenberg, Hamed Hamed, Borger Borger, Vatter Vatter, Surges Surges, Schoch Schoch, Becker Becker, Pitsch Pitsch
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