The frequency of intrathecal antibody production to Epstein-Barr virus (EBV) in multiple sclerosis (MS) patients is surprisingly low compared to that of other microbial agents. This was shown in a collaborative study between EUROIMMUN and scientists at Charité Universitätsmedizin Berlin. The finding is intriguing given the strong link between EBV and MS.
EBV is presumed to play a causal role in MS, but the underlying mechanisms remain unclear. The most characteristic laboratory finding in MS is intrathecal production of immunoglobulin G (IgG), which is present in 90% of patients. The intrathecally produced IgG is polyspecific and directed in part against various microbial antigens, for instance measles, rubella and varicella zoster virus (VZV), which is referred to as MRZ reaction. The MRZ reaction is the most specific laboratory marker of MS to date.
The researchers investigated the seroprevalences and frequencies of intrathecally produced antibodies to EBV compared to ten other microbes in MS patients. Besides the MRZ parameters, the other microbes encompassed Borrelia burgdorferi, cytomegalovirus, herpes simplex virus type 1/2, mumps virus, parvovirus B19, tick-borne encephalitis virus and Toxoplasma gondii. Antibodies were determined in paired cerebrospinal fluid (CSF) and serum samples using EUROIMMUN ELISAs. Intrathecal antibody production was assessed by calculating antibody indices according to standard formula.
All (100%) of the MS patients were EBV seropositive. Seroprevalences for the other 10 microbes in the MS patients ranged from 94% for VZV to 6% for B. burgdorferi. The frequency of intrathecally produced antibodies in patients who were seropositive for the respective microbe amounted to roughly 40% for measles, rubella, mumps and VZV, 70% for parvovirus B19 and only 10% for EBV. The frequency of intrathecally produced antibodies to EBV was lowest among all the investigated microbes.
The findings of the study are seemingly paradoxical but underscore the unique role of EBV in MS. The authors hypothesise that the B cells responsible for intrathecal antibody production are primed during and through acute EBV infection to enter the central nervous system (CNS) of MS patients. As there are no antibody-producing cells in the CNS under physiologic conditions, these cells must migrate from the systemic circulation. Only B cells from previous infections and vaccinations are available to be primed to enter the CNS. At the timepoint of acute EBV infection, EBV antibody-producing cells are not yet available for priming. Future studies may investigate the history of infections in relation to primary EBV infection in MS patients to correlate this with intrathecal antimicrobial antibody production.
A further important finding from the study was that adding mumps virus and parvovirus B19 to the MRZ reaction increased the sensitivity from 34% to 52%. This suggests that the extended panel, known as MRZ-UP, may increase the diagnostic value of the MRZ reaction for MS.
Read more about the study in the journal Neurology Neuroimmunology & Neuroinflammation:
Pache F et al. Broad Analysis of Serum and Intrathecal Antimicrobial Antibodies in Multiple Sclerosis Underscores Unique Role of Epstein-Barr Virus. Neurol Neuroimmunol Neuroinflamm 12(1):e200332 (2025). DOI: 10.1212/NXI.0000000000200332. Epub 2024 Nov 27. PMID: 39602676; PMCID: PMC11616972.