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Updated: Jun 23, 2026
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Published on: December 1, 2023
Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI
R A Farrell1, D Antony, G R Wall
1Department of Neuroinflammation, Institute of Neurology, UCL, Queen Square, London, UK. r.farrell@ion.ucl.ac.uk
Background:
Evidence suggests that Epstein-Barr virus (EBV) plays a role in triggering or perpetuating disease activity in multiple sclerosis (MS).
Methods:
We investigated 100 subjects (50 clinically isolated syndrome [CIS], 25 relapsing-remitting [RR] MS, 25 primary progressive [PP] MS) for 1) evidence of EBV reactivation and 2) disease activity as indicated by serial gadolinium (Gd)-enhanced MRIs over a 5-year period. EBV DNA in blood was quantified by real-time quantitative PCR and EBV serology for anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG), anti-viral capsid antigen (VCA) IgG, and anti-EBV IgM. Data were analyzed using repeated measures analysis, analysis of variance, and logistic regression analysis.
Results:
All subjects had serologic evidence of previous EBV infection, but no lytic reactivation was detected. Significant differences in EBNA-1 IgG titers were found between subgroups, highest in the RRMS cohort compared with PPMS (p < 0.001) and CIS (p < 0.001). Gd-enhancing lesions on MRI correlated with EBNA-1 IgG (r = 0.33, p < 0.001) and EBNA-1:VCA IgG ratio (r = 0.36, p < 0.001). EBNA-1 IgG also correlated with change in T2 lesion volume (r = 0.27, p = 0.044) and Expanded Disability Status Scale score (r = 0.3, p = 0.035).
Conclusions:
The correlation between elevated Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) and gadolinium-enhancing lesions suggests an association between Epstein-Barr virus (EBV) infection and multiple sclerosis (MS) disease activity. The heightened immune response to EBV in MS is specifically related to EBNA-1 IgG, a marker of the latent phase of the virus. The lack of association between acute viral reactivation in the peripheral blood and Gd(+) lesions suggests a limited role of the former in driving disease activity.
Insights
Epstein-Barr virus (EBV) infection, specifically elevated EBNA-1 IgG, correlates with multiple sclerosis (MS) disease activity. Acute EBV reactivation in blood showed no link to MS lesions, suggesting a role for latent EBV in disease progression.
Area of Science:
- Neuroimmunology
- Viral Immunology
Background:
- Epstein-Barr virus (EBV) is implicated in multiple sclerosis (MS) pathogenesis.
- Understanding the specific viral mechanisms driving MS activity is crucial.
Purpose of the Study:
- To investigate the association between EBV reactivation and MS disease activity.
- To determine if EBV serology markers correlate with MRI-defined disease activity over 5 years.
Main Methods:
- Studied 100 subjects with clinically isolated syndrome (CIS) or MS (RRMS, PPMS).
- Assessed EBV DNA, EBV serology (EBNA-1 IgG, VCA IgG, EBV IgM), and serial MRI (Gd-enhancing lesions) over 5 years.
- Utilized quantitative PCR, serological assays, and statistical analyses (repeated measures, ANOVA, logistic regression).
Main Results:
- All subjects showed prior EBV infection; no lytic reactivation was detected.
- Elevated EBNA-1 IgG titers were significantly higher in RRMS compared to PPMS and CIS cohorts.
- EBNA-1 IgG and EBNA-1:VCA IgG ratio correlated significantly with Gd-enhancing lesions and T2 lesion volume.
- EBNA-1 IgG also correlated with Expanded Disability Status Scale scores.
Conclusions:
- Elevated EBNA-1 IgG, a marker of latent EBV infection, is associated with MS disease activity, including new inflammatory lesions.
- The heightened immune response to EBV in MS patients is specifically linked to EBNA-1 IgG.
- Acute EBV reactivation in peripheral blood does not appear to drive MS disease activity.
