Hunting for Viral Responses in MS, yes you can find responses to EBV, but they are nothing special just to MS.

MS= multiple sclerosis, HV = healthy volunteer, TSP = Tropical spastic paraparesis (caused by HTLV1) (Enose-Akahata et al. 2023)

Whilst the crusade for EBV and MS gains momementum, the question I posed just before Christmas was “Is there anything special about EBV and MS or will EBV associate with other conditions?” Because if it does, then the approaches to deal with EBV to treat MS may not be so simple. Importantly, if it is is important the question is when is it important? Because if it is the cause, is it important before MS shows itself then treatments need to be focused there. We have seen a lot of vitamin D trials in MS and other conditions that really didn’t go anywhere, when the the biology was arguing for a more major influence much earlier. I think we need the right trials not the easy trials.

In this study they go hunting for evidence of responses to viruses in MS, healthy people and people with another neurological condition (TSP) known to be related to a known viral infection. They use a tool to find responses to viruses in the blood and the spinal fluid and they can find evidence for responses for the known virus type that causes the non-MS neurological disease (Tropical Spastic paraparesis). So the technology works for virus hunting. This virus is not a part of the MS response, but when it comes to MS, yes there maybe be some elevated response to EBV in MS compared to the healthy individuals, however they elevated find responses to EBV in the other conditions There is no single MS viral response and there is nothing special in the type of responses in MS that can’t be found in the other neurological conditions. However, there is a signature of viral infections.

This warns us , if you do science when you do not look for alternative answers, you are only going to see the reality you want to see. So you are doing science you want to prove. You should be trying to disprove your idea and if you do…..get a new idea. However, this is seldom done. My idea that EBV can be important in conditions outside of MS remains intact. Next experiment anyone.

In this study they look at responses to hundreds of viruses and see responses to multiple viruses. Now it doesn’t say that EBV is not the cause of MS, but it provides no evidence that MS is specific to EBV infection.

Enose-Akahata Y, Wang L, Almsned F, Johnson KR, Mina Y, Ohayon J, Wang XW, Jacobson S. The repertoire of CSF antiviral antibodies in patients with neuroinflammatory diseases. Sci Adv. 2023; 9(1):eabq6978.  Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although various viruses have been proposed to contribute to MS pathology, the aetiology of MS remains unknown. Since intrathecal antibody synthesis is well documented in chronic viral infection and neuroinflammatory diseases, we hypothesized whether the patterns of antigen-specific antibody responses associated with various viral exposures may define patients with CNS chronic immune dysregulation. The pan-viral antibody profiling in cerebrospinal fluid (CSF) and serum of patients with MS showed significant differences from those in healthy volunteers and a pattern of antibody responses against multiple viruses, including the previously identified Epstein-Barr virus. These findings demonstrate that virus-specific antibody signatures might be able to reflect disease-associated inflammatory milieu in CSF of subjects with neuroinflammatory diseases.

They say “To date, a number of infectious viruses, including measles, mumps, Epstein-Barr virus (EBV), human herpesvirus, and other ubiquitous human herpesviruses, have been proposed to contribute to MS pathology, although not one virus has been definitively shown to be the causative agent . In particular, a link between EBV and MS has long been suspected, and recently, this association has again re-emerged based on recent reports demonstrating increased EBV-specific antibodies in serum of patients with MS”.

They say “…it is unclear whether antibody responses against EBV are uniquely elevated in MS and what is the extent of EBV reactivity in the CSF of patients with MS?……In addition, it has been suggested that virus-specific immune responses may cross-react with self-antigens (molecular mimicry), thus contributing to the pathophysiology of the disease”.

We here hypothesize that if environmental factors including virus infections and immune reactivation against viruses play a role as “triggers” in MS, then antibody signatures against such viral exposures may be defined that represent immunological signatures in patients with MS.

To identify virus-specific antibody signatures, they tested spinal fluid and paired blood (serum) of MS patients and healthy normal volunteers (HVs) using VirScan, an established platform for the profiling of the entire known human virome (viruses present in humans) that detects response to 206 known human pathogenic viruses.

First they went hunting for viruses in Tropical spastic paraparesis and they found the virus subgroup (HTLV1) known to be a causative agent and they didn’t find it in MS. Then they hunted in MS and didn’t find any antibody response against any single virus specific for MS that couldnt be found in controls and whilst there was increased responses to EBV in MS, these could be found in other people too.

Are multiple viruses triggering multiple autoimmunities? I don’t think you have to evoke this view

CoI: None relevant

Disclaimer: These are the views of the author

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  • For me, the questions are these

    1 What of seroconversion studies published in elite journals that focused on EBV, looking at 10 MILLION US army personnel that were followed over 20 YEARS which showed a x 32 fold increased risk ?
    2 What of EBV promoting cancer and autoimmune disease in at-risk populations ?
    3 What about EBV reprogramming latently infected B cells ? And chronic presentation of viral Ags as a potential source of autoreactivity ?
    4 How about high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the CNS protein glial cell adhesion molecule (GlialCAM) that perhaps provide the structural and in vivo functional evidence for its relevance ? Are all of the above points irrelevant ?

    I think there is such a thing as ‘excessive analysis’ till everything becomes suspect. I am not sure that the ‘other viruses’ have been studied and pursued w such vigor as EBV has been. Now I am curious that EBV and NPC (nasopharyngeal carcinoma) are related…… that a cock and BS story too ?

    • 1. You get all sorts of stuff published in elite journals that is best used for toilet paper such as…..OK not going there today:-). However the list of irreproducibility is quite large:-(
      1. You get infected with EBV before you get MS….but that does not say that targting EBV once you have MS is of any relevance so in which case it would not matter if there were EBV antibodies in blood or brain. The antibodies were in TSP too so what is specific? In the US army study, what they did not do was look for anything but MS…so they sort of knew what they were looking for before they did it…I seem to remember that not every body had EBV response?, is that because of detection issues or does the argument breakdown?. Anyway I wrote to them to ask why and they said the cost was too much….Em. Again by not looking it allows me to say their obervations would be replicated in Lupus, Sorjrens arthrtis etc. There is nothing special about MS. The story is better developed in MS
      2. Yes and as above, once caused you dont need antibodies to EBV and again says nothing special about MS….The virus mimics B cell signalling molecules…not surprising you get cancers and I have said autoimmunity.
      3. Presentation of viral antigens sure, but what is different from CMV, cold, flu and any other B cell/immmune cell infection etc. I once did an EM study of mouse cell lines because I made a B cell line and it was fizzing with virus and so scared me. I used alot of Virkon to kill virus and shut down the cells and stopped using them incase the virus was dangerous. I thin did a similar study looking at common immunological cell lines, like those used for making monoclonal antibodies e.g NS-1 lines, and every single one of the commonly used cells that I looked at showed that the cells were producing viral particles which I could see in electron microscopy….maybe that is why they are immortal lines.
      4.Where is the proof that any of this is important and may be sencondary to damage? EBNA1 and glialcam…why is MS not a problem of astrocytes as glialcam is express by astrocytes at a much higher level and doing the same experiment others find cross reactivity to and endothelial cell marker…So lets see others find the same thing as we have been there countless times before. Rememnver 4.1 antibodies? It is have an antibody and then hunt for something plausible, we know that if you take antibodies from people with MS they bind to all sorts of CNS targets.

      However even if true again does the level of anti-EBV matter?…isn’t MS a T cell disease after all?:-)
      Once you get glialcam reactivity who cares about EBV?. I thought the alpha B hypothesis was more plausible and fit the data better, but that is now probably a dead duck as the trial failed. The patent situation is problematical:-(

      Yes I am playing devils advocate but I am sorry I dont think this is excessive analysis….One can put the ugly sisters foot into Cinderella’s slipper to get a sexy publication.

      As for EBV and carcinoma sure EBV infects epithelia and there is hodgkins/burkitts lymphoma and EBV and EBV and MS. I dont think one questions that EBV is involved in the pathogenesis but the key question is how and when, because get it wrong and your trials fail….too many failures and no-one is interested anymore

      • I guess the elite journal in this case is Science (Bjornevik, Alberto Ascherio, Munger, et al). CMV infection did NOT alter risk of MS, and EBV seroconversion was accompanied by sNfL levels too. At baseline, 35 cases that eventually had MS, were seronegative. In f/u, all of them seroconverted before MS onset. HR for MS comparing EBV seroconversion vs persistent EBV seroneg status was 32.4.

        CMV infection did NOT alter risk of MS.

        There are so many unresolved issues in MS, obviously – it is B or T cell mediated disease ? Is X linked agammaglobulinemia protective in MS ? Obviously both B and T cells are needed for MS and T cell theories have been upended by B cell therapies and BTK inhibitors cannot be far behind in the armamentarium of MS therapies advancing the B cell hypothesis in MS.

        • Thanks….I remember “The high seroconversion rate among individuals who developed MS during follow-up (97%) contrasts with the 57% rate of seroconversion observed among individuals who did not develop MS (Fig. 2A)”, but not figure 3S…however the Bjornevik et al. paper didn’t really tell us much that was new that wasn’t known a decade earlier…Levin et al Ann. Neurol. 2010; 67: 824. 305 individuals who developed MS and 610 matched controls selected among the >8 million active-duty military personnel whose serum has been stored in the Department of Defense Serum Repository. Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative. All of the 10 EBV-negative cases became EBV positive before MS onset; in contrast, only 35.7% (n = 10) of the 28 controls with follow-up samples seroconverted (exact p value = 0.0008).

          I have no issue that you get infected with EBV before you get MS and not CMV, but the question relates to the immunological studies and how EBV is involved

  • Nice reasoning

    Like this bit

    Now it doesn’t say that EBV is not the cause of MS, but it provides no evidence that MS is specific to EBV infection.

    Could this be Ebv is necessary but not sufficient ,kind of scenario?

    Nice post

    • There are alot more people infected with EBV than have MS (or other autoimmunities) so would agree you need more than just infection

      • The aetiology of MS is complex and multifactorial,
        involving the interplay of known genetic susceptibility
        factors, predominantly in genes directing the immune
        system, and environmental factors, including infectious
        agents, lack of sun exposure and vitamin D, smoking
        and obesity.

        Infectious agents were first suspected
        in the aetiology of MS soon after its classification as a
        discrete clinical entity in the late 1800s.

        The heterogeneity
        and the evolution of the disease throughout a
        patient’s lifetime and within the MS lesion itself have
        further obscured the identification of a single infectious
        agent as a consistent disease trigger. Nevertheless, epidemiological,
        serological and virological evidence has
        accumulated to support the role of EBV in the aetiology
        of MS, with recent large population- based studies
        demonstrating that EBV infection is likely a prerequisite
        for disease…………..Nature Reviews, August 2022, The Wistar Institute

  • A bit late, been tending to a pummeled auto, and the holidays. Not that I have anything against complicated science that’s hard to follow, that’s where it’s at most of the time. For me, the question is not whether EBV causes MS, but, why did I get MS when something like 97% or more of the others with EBV, did not?

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