BOSTON — Only a small proportion of patients infected with the Epstein-Barr virus (EBV) develop multiple sclerosis (MS). A new military study sought to determine why that is and what the underlying mechanisms are.
The goal of the research led by the Harvard T.H. Chan School of Public Health in Boston and involving the Uniformed Services University of the Health Science in Bethesda, MD, was to:
- assess the serologic response to all EBV peptides before the first symptoms of MS occur,
- determine whether the disease is associated with a distinct immune response to EBV, and
- evaluate whether specific EBV epitopes drive this response.
The prospective, nested case-control study, used serum samples from U.S. military personnel stored in the DoD Serum Repository. The 30 servicemembers with MS had serum collected at a median one year before onset (reported to the military in 2000-2011) and were matched to 30 controls for age, sex, race and ethnicity, blood collection and military branch. Their mean (SD) age at sample collection was 27.8 (6.5) years; 46 of 60 participants (76.7%) were male. The data were analyzed between Sept. 1, 2022, and Aug. 31, 2023, and results were published in JAMA Neurology.1
The focus was on antibodies (enrichment z scores) to the human virome measured using VirScan (phage-displayed immunoprecipitation and sequencing).
The study team estimated rate ratios (RRs) for MS for antibodies to 2,263 EBV peptides (the EBV peptidome) using conditional logistic regression, adjusting for total anti-EBV nuclear antigen 1 (EBNA-1) antibodies, which have consistently been associated with a higher MS risk. They also explored the role of antibodies against other viral peptides.
The results indicated that the antibody response to the EBV peptidome was stronger in individuals with MS but without a discernible pattern.
“The antibody responses to 66 EBV peptides, the majority mapping to EBNA antigens, were significantly higher in preonset sera from individuals with MS (RR of highest vs. lowest tertile of antibody enrichment, 33.4; 95% CI, 2.5-448.4; P for trend = 0.008),” the researchers explained. “Higher total anti-EBNA-1 antibodies were also associated with an elevated MS risk (top vs bottom tertile: RR, 27.6; 95% CI, 2.3-327.6; P for trend = 0.008). After adjusting for total anti-EBNA-1 antibodies, risk estimates from most EBV peptides analyses were attenuated, with 4 remaining significantly associated with MS, the strongest within EBNA-6/EBNA-3C, while the association between total anti-EBNA-1 antibodies and MS persisted.”
The authors concluded that, based on their findings, “antibody response to EBNA-1 may be the strongest serologic risk factor for MS. No single EBV peptide stood out as being selectively targeted in individuals with MS but not controls. Larger investigations are needed to explore possible heterogeneity of anti-EBV humoral immunity in MS.”
- Cortese M, Leng Y, Bjornevik K, Mitchell M, et. Al. Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis. JAMA Neurol. 2024 May 1;81(5):515-524. doi: 10.1001/jamaneurol.2024.0272. PMID: 38497939; PMCID: PMC10949154.