Antibody Properties Associate with Clinical Phenotype in LGI1 Encephalitis

Area of Science:

• Neuroimmunology
• Molecular Neuroscience

Background:

• Autoimmune encephalitis (AE) linked to LGI1 autoantibodies presents heterogeneously, with phenotypes including faciobrachial dystonic seizures (FBDS) and limbic encephalitis (LE).
• The underlying reasons for this phenotypic variability in LGI1-associated AE remain poorly understood.

Purpose of the Study:

• To investigate how autoantibodies against LGI1 (LGI1 abs) from patients with different AE phenotypes (LE vs. FBDS) interact with the LGI1 protein.
• To elucidate the functional consequences of these distinct autoantibody-epitope interactions on hippocampal neuronal function and synaptic plasticity.

Main Methods:

• Characterization of LGI1 autoantibodies from LE and FBDS patients using single amino acid epitope mapping.
• Electrophysiological recordings (long-term potentiation, short-term plasticity) in mouse hippocampal slices.
• Measurement of hippocampal synaptic density and postsynaptic receptor (AMPA-R, NMDA-R) clustering.

Main Results:

• LGI1 abs from LE patients primarily targeted the Leucine-rich repeat domain, while abs from FBDS patients recognized both Leucine-rich repeat and Epitempin domains.
• Incubation with LE patient LGI1 abs significantly impaired long-term and short-term synaptic plasticity and reduced hippocampal synaptic density.
• FBDS patient LGI1 abs did not significantly affect synaptic plasticity or density, and no decrease in AMPA-R or NMDA-R clusters was observed.

Conclusions:

• Phenotype-specific LGI1 autoantibodies exhibit distinct epitope recognition patterns.
• These differences in antibody binding lead to disparate functional effects on hippocampal neurons and synaptic structures.
• This study provides insights into the molecular mechanisms driving phenotypic heterogeneity in LGI1-associated autoimmune encephalitis.