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

From the Department of Neuroinflammation (R.A.F., L.F., J.S., K.S., D.H.M., G.G.), NMR Research Unit (L.F., J.S., Z.K., K.S., D.H.M.), and Department of Brain Repair and Rehabilitation (Z.K.), Institute of Neurology, University College London; Neuroimmunology Unit (R.A.F., D.A., G.G.), Neuroscience Centre, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry; and Department of Virology (G.R.W., D.A.C.), Barts and the London NHS Trust, London, UK.

Address correspondence and reprint requests to Dr. Rachel Farrell, Department of Neuroinflammation, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK r.farrell{at}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.

Abbreviations: CI = confidence interval; CIS = clinically isolated syndrome; CMV = cytomegalovirus; EBNA-1 = Epstein-Barr virus nuclear antigen 1; EBV = Epstein-Barr virus; EDSS = Expanded Disability Status Scale score; FOV = field of view; Gd = gadolinium-DTPA; HLA = human leukocyte antigen; IgG = immunoglobulin G; IL = interleukin; IQR= interquartile range; MHC = major histocompatibility complex; MS = multiple sclerosis; OCB = oligoclonal IgG bands; OR = odds ratio; PHV-1 = phocine herpesvirus type 1; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; TE = echo time; TR = repetition time; VCA = viral capsid antigen; VZV = varicella zoster virus.

Supplemental data at www.neurology.org

Editorial, page 13

e-Pub ahead of print on May 20, 2009, at www.neurology.org.

Supported by the MS Society of Great Britain and Northern Ireland.

Medical Devices: 1.5-T GE scanner (General Electric, Milwaukee, WI); 7500 real-time PCR system (Applied Biosystems, Warrington, UK); QiaCube with QIAmp DNA blood mini kit (Qiagen, Hilden, Germany).

Disclosure: Author disclosures are provided at the end of the article.

Received July 29, 2008. Accepted in final form February 24, 2009.

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				J. D. Lunemann and A. Ascherio Immune responses to EBNA1: Biomarkers in MS? Neurology, July 7, 2009; 73(1): 13 - 14. [Full Text] [PDF]