Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM

Area of Science:

• Neuroimmunology
• Virology
• Molecular Mimicry

Background:

• Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system.
• B cells in cerebrospinal fluid (CSF) contribute to MS inflammation.
• Epstein-Barr virus (EBV) is epidemiologically linked to MS, but its role is unclear.

Purpose of the Study:

• To investigate the molecular mechanism linking EBV to MS.
• To identify cross-reactive antibodies between EBV and central nervous system proteins.
• To provide structural and functional evidence for molecular mimicry in MS pathogenesis.

Main Methods:

• Single-cell sequencing of B cell repertoires from MS patients.
• Protein microarray testing of CSF-derived antibodies against viral antigens.
• Crystal structure determination of EBNA1-GlialCAM epitope-antibody complex.
• In vivo studies using a mouse model of MS.

Main Results:

• Identified high-affinity molecular mimicry between EBV's EBNA1 and GlialCAM.
• Demonstrated antibody cross-reactivity due to molecular mimicry.
• Showed EBNA1 immunization exacerbates MS in a mouse model.
• Found prevalence of anti-EBNA1 and anti-GlialCAM antibodies in MS patients.

Conclusions:

• Established a mechanistic link between EBV infection and MS pathogenesis.
• Molecular mimicry between EBNA1 and GlialCAM is a key factor.
• Findings may inform novel therapeutic strategies for MS.