Molecular pathomechanisms of immune-mediated epileptogenesis

Abstract

This thesis explores the immune-mediated and molecular mechanisms underlying AE and epileptogenesis, with a particular emphasis on T cell-dependent neuroinflammation and the transcriptional dynamics across different stages of disease progression. AE, especially subtypes associated with intracellular autoantibodies, represents a contributor to the development of TLE. However, the precise immunopathological processes, including the initiation and maintenance of disease by T cells, remain incompletely understood. Moreover, beyond the context of AE, the broader mechanisms driving epileptogenesis involve complex, stage-specific molecular changes that are not yet fully characterized.<br /> Although anti-GAD65 and anti-Drebrin-positive TLE patients display similar neuropathological features, they exhibit distinct immunopathogenic mechanisms. Single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue reveals that inflammatory signaling diverges between the subtypes: NF-κB pathway activation predominates in anti-GAD65-positive cases, while anti-Drebrin-positive patients show enrichment of FoxO-associated cascades. These differences might be reflected in distinct microglial phenotypes and correlate with varying clinical responses to therapy, underscoring the relevance of immune context in disease progression and therapeutic outcome.<br /> Transcriptomic analyses in a T cell–mediated AE model further demonstrate that T cell activity alone, even in the absence of autoantibodies, is sufficient to trigger neuroinflammatory cascades, neuronal dysfunction, and early epileptogenic signatures. These findings underscore the central role of T cells and highlight shared downstream mechanisms between AE and broader forms of epilepsy. BBB dysfunction, which facilitates peripheral immune cell infiltration and disrupts the neurovascular niche, emerges as a critical factor in disease evolution. These targeted immune responses are accompanied by persistent BBB disruption, astrocytic paracrine dysfunction and leukocyte-driven inflammation. Moreover, cytotoxic T cell attack directed against GABAergic interneurons demonstrate to induce hallmark features of temporal lobe epilepsy TLE, including dentate gyrus granule cell dispersion and mossy fiber dysfunction. These findings show that T cell responses, shaped by the neuronal subtype they target, influence disease trajectories.<br /> Furthermore, an in-depth analysis of early epileptogenesis using the pilocarpine-induced SE model of chronic TLE, highlights transcriptional cascades driven by immediate early genes and key regulators such as NFKB1, IRF8, and Spi110. These factors, activated shortly after seizure onset, initiate cell type–specific gene expression programs that promote sustained neuroinflammation and neuronal hyperexcitability. Despite differences in initiating insults and immune triggers, these molecular responses converge onto shared downstream pathways that define epileptogenic networks.<br /> Taken together, this work identifies shared inflammatory and excitability-related mechanisms across AE and epileptogenesis, despite differing initiating triggers. Central elements include microglial activation, BBB disruption, and transcriptional programs driven by NF-κB and FoxO pathways. These findings underscore the potential of multi-targeted therapies such as GLP-1 receptor agonists and antioxidants to modulate both immune and oxidative stress responses. By identifying key molecular drivers, this thesis supports the development of precision medicine approaches to AE and epilepsy.