Intrathecal B-cell activation in LGI1 antibody encephalitis

Area of Science:

• Neuroimmunology
• Immunology
• Neurology

Background:

• Leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis is often characterized by serum-predominant antibodies and a lack of typical inflammatory markers in cerebrospinal fluid (CSF).
• This pattern suggests a peripheral immune response, but the role of B cells within the central nervous system (CNS) remains unclear.

Purpose of the Study:

• To investigate intrathecal B-cell activity and immune repertoire characteristics in patients with LGI1 antibody encephalitis.
• To determine if B cells within the CNS contribute to the pathogenesis of LGI1 antibody encephalitis.

Main Methods:

• Collected paired CSF and peripheral blood (PB) mononuclear cells from 6 patients with LGI1 antibody encephalitis and 2 controls.
• Performed deep B-cell immune repertoire sequencing on immunoglobulin heavy chain transcripts.
• Quantified LGI1 antibody levels in CSF and PB.

Main Results:

• Despite lower antibody titers in CSF compared to serum, deep B-cell repertoire analysis revealed a restricted CSF repertoire with extensive clusters of clonally related B cells.
• These clusters exhibited significant mutational activity, indicating an independent, antigen-driven B-cell response within the CNS.
• No such CNS-based response was observed in control patients.

Conclusions:

• Intrathecal immunoglobulin repertoire expansion is a key feature of LGI1 antibody encephalitis.
• The findings support an intrinsic CNS immune response in LGI1 antibody encephalitis.
• Suggests the need for CNS-penetrant therapies to effectively manage LGI1 antibody encephalitis.