Duncan Salmon

Background: Multiple Sclerosis (MS) is a neurological disease characterized by demyelination and oligodendrocyte damage within the Central Nervous System (CNS)¹. Patients typically present with unilateral optic neuritis, internal ophthalmoplegia, ataxia, and the production of intrathecal IgG known as oligoclonal bands². These symptoms manifest as T2-FLAIR white matter hyperintensities whose appearance and locations correlate with disease progression. Infection by the Epstein Barr Virus (EBV), which targets B cells and causes infectious mononucleosis, has long been suspected as a potential trigger for developing MS³. Retrospective studies back this claim: an analysis of approximately 62 million serum samples collected from US servicemen between 1993 and 2013 showed a hazard ratio of 32x between EBV infection and MS⁴. Now, new research shows that MS oligoclonal bands develop autoreactivity through molecular mimicry of the Epstein Barr Nuclear Antigen 1 (EBNA1) with the CNS adhesion molecule GlialCAM. This discovery suggests a definitive immunological link between EBV infection and MS development.

Search Methods: CSF and post-mortem brain samples of MS patients were screened against Phage-Display Random Peptide Libraries in order to determine general antigen binding specificity^5,6. HuProt and PhIP-seq assays were performed to compare oligoclonal anti-EBNA1 antibodies with over 16,000 human proteins to determine oligoclonal band cross-reactivity towards host antigens⁷.

Results: Phage-Display Random Peptide Library assays showed that oligoclonal bands bind to various epitopes sharing sequence homologies with viral, apoptotic, and inflammatory proteins⁵. Moreover, these antibodies bind to EBNA1 and EBNA2; Brain IgG binds to both EBNA1 and EBNA2 while CSF IgG only binds to EBNA1⁶. The HuProt Assay and PhIP-seq assays show that anti-EBNA1 oligoclonal antibodies bind to GlialCAM through a shared Pro/Arg-rich AA394-399 region epitope. This cross-reactivity between viral and host antigens only occurs after B cell somatic hypermutation⁷.

Conclusions: MS oligoclonal bands bind to various antigens including EBNA1^5,6. EBNA1 has sequence homology with GlialCAM that causes cross-reactivity characteristic of an autoimmune molecular mimicry response⁷. This establishes a potential biochemical and immunological link between EBV infection and MS development. More research is required to fully establish this pathway and EBV’s true role in MS, but the discovery nonetheless offers rich opportunities for developing new therapeutics targeting this relationship.

Works Cited:

1. Rodríguez Murúa S, Farez MF, Quintana FJ. The Immune Response in Multiple Sclerosis. Annu Rev Pathol. 2022;17:121-139. doi:10.1146/annurev-pathol-052920-040318
2. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review [published correction appears in JAMA. 2021 Jun 1;325(21):2211]. JAMA. 2021;325(8):765-779. doi:10.1001/jama.2020.26858
3. Hoover K, Higginbotham K. Epstein Barr Virus. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559285/
4. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222
5. Graner M, Pointon T, Manton S, et al. Oligoclonal IgG antibodies in multiple sclerosis target patient-specific peptides. PLoS One. 2020;15(2):e0228883. Published 2020 Feb 21. doi:10.1371/journal.pone.0228883
6. Wang Z, Kennedy PG, Dupree C, et al. Antibodies from Multiple Sclerosis Brain Identified Epstein-Barr Virus Nuclear Antigen 1 & 2 Epitopes which Are Recognized by Oligoclonal Bands. J Neuroimmune Pharmacol. 2021;16(3):567-580. doi:10.1007/s11481-020-09948-1
7. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7