Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI

Abstract

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.

Figure 1 Pattern of humoral response in clinical subgroups (A) Box plot of Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) (U/mL) by clinical subgroup. Median value and 95% confidence interval indicated. There are significant differences between subjects with relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS), and also between subgroups with RRMS and clinically isolated syndrome (CIS). (B) Box plot of viral capsid antigen (VCA) IgG (U/mL) by clinical subgroup. VCA levels were highest in PPMS. Significant differences were detected between CIS/PPMS and between RRMS/PPMS. (C) Box plot of EBNA-1 IgG titer in patients with non-active vs patients with active MRI. Samples from patients with active MRI had higher levels of anti-EBNA-1 IgG. (D) Comparison of the ratio of anti-EBNA-1:VCA IgG titers in patients with non-active/active MRI.

Figure 2 Scatterplot of log (number of gadolinium-enhancing lesions + 1) and ratio of anti-EBNA-1:VCA IgG