Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Area of Science:

• Neuroimmunology
• Molecular Neuroscience

Background:

• Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is a common antibody-mediated encephalopathy.
• Limited understanding of the intrathecal B-cell autoimmune response in LGI1 encephalitis.

Purpose of the Study:

• To characterize the intrathecal B-cell autoimmune response in LGI1 encephalitis.
• To investigate the pathogenic effects of single LGI1 antibodies.

Main Methods:

• Cloning and expression of antibodies from cerebrospinal fluid (CSF) B cells of LGI1 encephalitis patients.
• Testing LGI1 antibody reactivity, isotype, affinity maturation, and blockade of LGI1-ADAM22 interaction.
• Assessing the effect of LGI1 antibodies on hippocampal neuron excitability in slice cultures.

Main Results:

• LGI1-reactive antibodies were frequent in antibody-secreting cells (ASCs) and memory B cells.
• All identified LGI1 antibodies were IgG isotypes and affinity-matured.
• LGI1 antibodies, regardless of ADAM22 interaction blocking, increased neuronal excitability.

Conclusions:

• The intrathecal autoimmune response in LGI1 encephalitis is primarily driven by LGI1 antibodies.
• LGI1 antibodies are sufficient to promote neuronal excitability, contributing to seizure generation.
• Distinct autoantibody profiles highlight the heterogeneity of autoimmune encephalitides.