The active intrathecal B-cell response in LGI1-antibody encephalitis

Area of Science:

• Neuroimmunology
• Molecular Immunology
• Autoimmune Neurology

Background:

• Leucine-rich glioma inactivated 1 (LGI1) antibodies are linked to immunotherapy-responsive encephalitis and epilepsy.
• Antibody concentrations are significantly higher in serum than cerebrospinal fluid (CSF).
• The origin of B cells producing LGI1 antibodies and their CNS entry remains unclear.

Purpose of the Study:

• To investigate the migration and expansion of peripheral and central B cells in the production of LGI1-specific IgG.
• To understand the B-cell dynamics in LGI1-antibody-associated autoimmune CNS diseases.

Main Methods:

• Deep immune repertoire sequencing of immunoglobulin heavy chain variable regions (Ig VH) from CSF and peripheral blood B cells.
• Bioinformatics clustering of IgM-VH and IgG-VH transcripts to analyze B-cell diversification.
• Comparison of intrathecal and peripheral B-cell repertoires in two patients with LGI1-antibody encephalitis.

Main Results:

• Identified clusters of related Ig-VH transcripts in the CSF of both patients.
• Observed somatic hypermutations within these CSF clusters, indicating B-cell maturation.
• Found numerous closely related Ig-VH clusters common to both CSF and peripheral blood, including dominant clusters suggesting active B-cell populations.

Conclusions:

• Suggests B-cell affinity maturation occurs within the CNS in LGI1-antibody encephalitis.
• Somatic hypermutation rates imply antigen-driven activation of B cells within the CSF.
• The specific antigen(s) driving this intrathecal immune response are yet to be identified.