No evidence for intrathecal IgG synthesis to Epstein Barr virus nuclear antigen-1 in multiple sclerosis

ackground: Recent studies suggest an intrathecal IgG response against Epstein Barr virus (EBV) in multiple sclerosis (MS), implicating a pathogenic role for the virus in MS. Objectives: To determine the spectrum of anti-EBV antibodies and B-cell epitopes within EBV nuclear antigen-1 (EBNA-1). Furthermore, to determine whether EBNA-1-specific IgG is produced intrathecally. Study design: Immunoblot analysis was used to study the anti-EBV IgG response in serum and cerebral spinal fluid (CSF) in MS and controls. EBNA-1 B-cell epitopes were identified by immunoscreening of 12 residue long peptides, with 11 residue overlap, spanning EBNA-1. Thirteen peptides containing all immunoreactive regions were constructed and used in paired serum and CSF of MS patients (n= 17) and controls (n= 18). Subsequently, reactivity to the identified immunodominant peptide was analysed in a large cohort of serum and CSF of MS patients (n= 114) and disease controls (n= 62). Results: No difference was observed in the overall anti-EBV antibody diversity, but EBNA-1 reactivity was increased in MS patients versus controls for immunoblot and ELISA (p<0.0001). Epitope analysis on EBNA-1 revealed one immunodominant region covering residues 394-451: EBNA-1394-451. Anti-EBNA-1394-451 IgG levels in serum and CSF were significantly higher in MS patients compared to controls. However, normalization for total IgG content of paired serum and CSF samples abrogated this disease association. Conclusions: MS patients have normal overall anti-EBV antibody responses with increased reactivity to EBNA-1394-451. No evidence was found for intrathecal EBNA-1-specific IgG synthesis in MS.

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