Characterization and Functional Analyses of Human Autoantibodies in Limbic Encephalitis
|
1 Universitätsklinikum Bonn, Institut für Neuropathologie |
|
Limbic encephalitis (LE) is increasingly recognized as a possible cause of chronic temporal lobe epilepsy (TLE) with neuropathological alterations in hippocampus and amygdala. This autoimmune disease is characterized by the occurrence of specific autoantibodies targeting neuronal surface or intracellular antigens causing recent onset seizures and memory impairment. However, only a fraction of patients with suspected LE show neural autoantibodies. Furthermore, the detailed mechanisms of epileptogenicity in autoantibody-mediated TLE are only partly understood and the differentiation of pathogenic cascades by which the individual autoantibodies convert hippocampal neuronal networks chronically hyperexcitable are still lacking. We analyzed biofluids of a cohort of 800 patients per year with diagnosed/suspected LE to identify novel autoantibodies. Immunoblotting assays were used by isolating antibody-antigen-complexes. This was followed by immunoprecipitation and autoantibody identification by mass-spectrometry. Additionally, in vitro analyses were performed in neuronal cell cultures to unravel if they cause structural defects and/or functional impairments. Patients’ sera were screened for unknown autoantibodies. We detected a high incidence for two newly identified autoantibodies: anti-Drebrin and anti-Munc18c. Anti-Drebrin is a molecule important for dendritic spine morphology and formation dynamics whereas anti-Mun18c plays a role in the presynaptic vesicle release. Subsequently, we investigated the cellular impact of autoantibody exposure on hippocampal neurons showing that human anti-Drebrin autoantibodies incubation altered postsynaptic Drebrin levels and distribution as well as neuronal excitability. Taken together, these results increase our understanding of the pathogenic significance of autoantibody induced LE. Complementary in vitro analyses suggest patient derived anti-Drebrin autoantibdies to induce impaired synapse composition and neuronal hyperexcitability. This work was generously supported by the Else Kröner-Fresenius-Stiftung.