Anne-Marie Datcu

Background: Multiple sclerosis (MS) is an autoimmune condition that affects the nervous system resulting in central nervous system (CNS) demyelination. ^1-4 MS is most common among females and typically affects adults aged 20 – 30 years old.^1-3,5 In recent epidemiologic studies, it has been shown there is a higher incidence of MS in the United States Black population, with a higher risk in black women. ³ Low vitamin D, childhood obesity, smoking and microbiome composition haven been shown to impact the risk of MS.³ HLA-DBR1*15:01 has been associated with risk of MS. ^3,6 It has been shown that Epstein Barr virus (EBV) infection is associated with the development of MS. ⁵ MS presents due to the initial inflammation of the CNS. Patients will often present with varying neurologic symptoms.^1,2,7 Differential diagnoses need to be considered since there are other disorders that mimic MS.² There is no cure for MS; current treatment predominantly includes FDA approved disease modification therapies to delay disease progression.^1,2 Despite identifying that EBV is critical in the development of MS, further research is being done to establish mechanisms of how EBV causes MS to identify revolutionary therapeutic approaches.

Objectives: The purpose of this review is to analyze research regarding proposed molecular mimicry mechanism occurring in MS patients after infection from EBV.

Methods:  An online literature search in the PubMed Database was conducted using the following MESH Terms: Multiple Sclerosis/ Immunology. Results were restricted to reviews, clinical studies, and abstracts published from 2018 – 2024. Articles were screened for relevance to molecular mimicry pathophysiology.

Results: One study examined the composition of B-cells in the CSF of MS patients in response to EBV and Epstein-Barr Nuclear Antigen 1 (EBNA).⁸ Authors observed B-cells encountered antigen and had undergone somatic hypermutation.⁸ IgM and IgG were associated with breakdown of the blood brain barrier. ⁸ CSF B-cells and plasma cells that have encountered antigen were also more likely to be of an inflammatory phenotype compared to peripheral counterparts, like TBX21, UBA7, and SDC1.⁹ EBNA1 on EBV is similar to GlialCAM so it also attacks the healthy GlialCAM in the immune response.⁸ Plasma of MS patients and healthy controls was analyzed for cross-reactivity with EBNA1 and GlialCAM.⁸ In the plasma cells of MS patients compared to healthy controls, reactivity to EBNA1 and to GlialCAM was increased.⁸ The presence of ANO2 antibodies in MS and is speculated to trigger a cytotoxic T-cell response.¹⁰ One study measured IgG antibody reactivity toward ANO2 and EBNA1.¹⁰  Anti-ANO2 antibodies were elevated in MS in comparison with controls.¹⁰ The mechanisms of how autoimmune response against ANO2 might act in MS is unclear, but it is hypothesized to be occurring through a similar molecular mimicry model. ¹⁰ One study found that T-cells were activated by EBNA 1 due to their sequence-relationship and may not be activated by B-Cells alone.⁸ T-cell that recognized GlialCAM and EBNA-1 produced granzyme & IFN- ⁸

Conclusion: Clarifying the molecular mechanisms that are involved in the interaction of MS and EBV can be utilized for future therapeutic developments.

Works Cited:

1. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review. Jama. Feb 23 2021;325(8):765-779. doi:10.1001/jama.2020.26858
2. Olek MJ. Multiple Sclerosis. Ann Intern Med. Jun 2021;174(6):Itc81-itc96. doi:10.7326/aitc202106150
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