Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls

Area of Science:

• Neuroimmunology
• Virology
• Autoimmunity

Background:

• Multiple sclerosis (MS) is an autoimmune CNS disorder potentially linked to Epstein-Barr virus (EBV) infection.
• The molecular basis for the EBV-MS connection, particularly molecular mimicry, remains incompletely understood.
• Previous work identified molecular mimicry between EBV nuclear antigen 1 (EBNA1) and CNS proteins ANO2, CRYAB, and GlialCAM.

Purpose of the Study:

• To investigate antibody responses against EBNA1 and CNS-mimic antigens in a large cohort of MS patients and controls.
• To confirm and further elucidate the molecular mimicry between EBNA1 and GlialCAM in the context of MS.
• To assess the combined influence of antibody responses, EBNA1 mimicry, and the HLA-DRB1*15:01 risk allele on MS susceptibility.

Main Methods:

• Analysis of IgG antibody responses against EBNA1, GlialCAM, CRYAB, and ANO2 in 650 MS patients and 661 controls.
• Utilizing blocking experiments to confirm cross-reactivity and molecular mimicry between EBNA1 and GlialCAM.
• Genotyping for the HLA-DRB1*15:01 allele and correlating antibody levels with MS risk and genetic factors.

Main Results:

• Elevated IgG responses against EBNA1 and the three CNS-mimic antigens (GlialCAM, CRYAB, ANO2) were associated with increased MS risk.
• Blocking experiments confirmed molecular mimicry between EBNA1 and GlialCAM, with evidence of epitope spreading.
• Antibody responses were elevated in MS patients with the HLA-DRB1*15:01 risk allele, and combined effects of antibodies and this allele significantly increased MS risk additively.

Conclusions:

• Molecular mimicry between EBNA1 and GlialCAM is a significant mechanism contributing to MS pathology.
• Specific antibody responses to EBNA1 and CNS-mimic proteins, particularly in conjunction with the HLA-DRB1*15:01 allele, are key factors in MS development.
• These findings highlight the role of EBV-driven autoimmunity in MS pathogenesis.