The season of MS: Glandular fever may not be linked to time of year

Vitamin D (as measured by time of year) and glandular fever are not linked. Should we be surprised?

I guess it boils down to how you think it is all working. 

If the month of birth theory holds any water then the major risk period is when you’re in the womb or shortly after birth. That the vitamin D hypothesis is also evident in type I diabetes suggests the risk factor is early in life. The biology suggests that vitamin D can shape your immune repertoire (range of different things your immune system responses to). So your die is cast as to whether you are at risk of autoimmunity. But this does not give you autoimmunity. Your other genes also put you at risk.

Whether vitamin D exhibits a major influence once the condition appears, remains to be seen. The trials are being done. 

Migration studies from low to high incidence countries suggest you acquire the trigger before you are 15 years for risk of MS. One suggestion is that this trigger is Epstein Barr Virus. This shapes your B cell (antibody making cells) repertoire. Which in turn may determine whether you get MS or other autoimmune conditions associated with EBV. 

About half the western population become infected with EBV in infancy. Are these the diabetes-prone people?  I guess infection goes unnoticed (undiagnosed) as one of the many episodes of fever that a child has. 

In adolescent life the naive/mature B cell gets infected by EBV because the virus enters the B cell via CD21 and an action via HLA-DR. Is this where the number one autoimmune genetic MS risk factor occurs? Is HLA-DRB1*1501 a gene that is good at getting B cells infected by EBV?

The mature B cell is then triggered to proliferate by the virus, and their killing by anti-EBV CD8, cytotoxic T cells cause a cytokine storm and sickness behaviour…that is glandular fever. 

The virus causes the B cells to mature into memory B cells and not antibody-producing plasma cells by a protein called EBNA3. 

The virus then hides in the memory B cells out of sight of the immune system, but switching off virus production. And as memory B cells are like buses that go round the body, the virus hitches a ride all round the body. 

However, the virus does other things, including making the memory B cell independent of the requirement of T cell help. So they do not need to get stimulated by a molecule called CD40. This means, for example, if a memory B cell enters the brain and sees its target it will become activated and so does not need a T cell of the same specificity to be present.

As more damage occurs, more antigens capable of stimulating B cells are liberated. You don’t have to postulate that it is one antigen causing the problem and these can change over time. However there is specificity because the B cell would have to see a brain derived signal to trigger release of cytokines to start the lesion.

This would be a great immune-evolution because it makes us more able to fight infection quickly, creating a survival advantage for the human population.

On the down-side, autoimmunity could occur. However, EBV has been with us for thousands of years (co-evolving with us). As humans used to have children earlier in life – and died earlier than we do now – autoimmunity would arguably not be selected against. Why? Because most autoimmunity occurs later in life (old-age and after child birth for our ancestors). 

So, evolution-wise, this would not be selected against. Furthermore, even if it did occur in our ancestors, it is at such a low frequency that it does not affect the overall survival of the population.  

What do you think of the idea?

Please post refuting (& supporting) work

Downham C, Visser E, Vickers M, Counsell C. Season of infectious mononucleosis as a risk factor for multiple sclerosis: A UK primary care case-control study. Mult Scler Relat Disord. 2017 Oct;17:103-106.

BACKGROUND:Infectious mononucleosis (IM) and vitamin D deficiency are both risk factors for multiple sclerosis (MS).
OBJECTIVE:We wished to establish if IM in the winter months when vitamin D levels are low may be a greater risk factor for MS than IM in the summer months.
METHODS:We identified all patients with MS diagnosed aged 16-60 in a large primary care database in the United Kingdom and matched each by age, sex, general practice and observation period with up to six controls. We identified a coded diagnosis of IM prior to the index date (date of diagnosis). Logistic regression was used to calculate the odds ratio for prior IM exposure in cases versus controls and for winter versus summer exposure in cases and controls with prior IM exposure.
RESULTS:Based on 9247 cases and 55,033 matched controls (246 and 846 with prior IM respectively), IM was associated with the development of MS (OR 1.77, 95%CI 1.53-2.05) but there was no evidence that IM in the winter as opposed to summer was associated with developing MS (OR 1.09, 95%CI 0.72-1.66).
CONCLUSION: We found no evidence that the season of IM influences the risk of subsequent MS.

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  • Very interesting thoughts, M.D. So, do you think that eliminating EBV might have detrimental effects for patients with autoimmune diseases?

    On the subject of eliminating EBV, I was doing some research on anti-EBV agents. Came across a very interesting paper from 1988 that explores the HIV drug AZT's effectiveness against EBV. Seems quite effective, and it has been noted that HIV-infected patients who are treated with AZT and AZT combo drugs have a much lower incidence of MS than the general population, and those with MS see a decrease in their disease activity. Would love your thoughts on this.

    Also found that AZT has been used to treat EBV -related cancers with some success. Again, thoughts?

    AZT is now off patent, and is available very cheaply in a drug called Combivir. Was actually thinking of talking to my neuro about giving this a try…

    • I would encourage you to read the linked to materials above. It appears that AZT induces the death of cells infected with EBV. Therefore, if EBV is indeed a driving factor in the MS disease process, and is primarily carried in B cells (memory B cells in particular), AZT could be an agent that would destroy the offending cells.

    • The fact that AZT an anti-HIV drug is only peripherally important here. The significant factor is that the drug is a very effective anti-EBV agent, and induces the death of cells infected with EBV. Therefore, it could kill the B cells that are suspected to contribute to the MS disease process.

      It could be that the Charcot project used the wrong anti-HIV drug (Raltegravir). Although the intent of using Raltegravir was to target MS related endogenous retroviruses, perhaps a better approach would be using a drug that targets EBV infected cells. Which seems to be precisely what AZT does.

      The fact that AZT is an anti-HIV drug is secondary to its apparent effectiveness in EBV lytic induction. This is why it is looks to be effective in treating EBV -related lymphomas. It kills the cancer cells infected with EBV, which in the case of non-Hodgkin's lymphoma appeared to be a similar set of cells that we are now zeroing in on as MS culprits.

      Would love to get thoughts on this from the researchers and clinicians that curate this blog…

    • Luiz may actually be the antiretrovirals that are blocking the activity of MS itself and not just the HIV. T
      his was even one of the research proposals in the beginning of the Charcot research.

      I even know a case here in Brazil of a person who became infected with HIV and then manifested MS. The MS only "calmed down" after it started treatment with the antiretrovirals, which are distributed free of charge in the country's public health network.

      Have you read anything about Prof. Michael Pender and Prof. Julian Gold?
      It's not worth reading about.

    • " antiretrovirals that are blocking the activity of MS itself and not just the HIV. T"

      Nice… So every pwms should get ART theraphy and we all be cured


    • In most untreated individuals, HIV infection leads to the progressive loss of CD4+ T cells.
      Several years ago, expression of the T-cell homeostatic cytokine IL-7 was shown to be dysregulated
      in HIV-infected individuals with advancing HIV-associated disease; increased serum
      levels of IL-7 were linked to decreased numbers of CD4+ T cells46,47. Although IL-7 is not
      absolutely essential for human B-cell development, it can induce the proliferation of human
      B-cell precursors48. Indeed, we have shown that high serum levels of IL-7 directly correlated
      with increased frequencies of immature transitional B cells in the peripheral blood of HIVinfected
      individuals (FIG. 1). These, in turn, directly correlated with HIV plasma viraemia and
      inversely correlated with CD4+ T-cell numbers49. High viral load and low CD4+ T-cell counts
      are thus associated with increased serum levels of IL-7 and increased numbers of immature
      transitional B cells (FIG. 2). A similar association between increased serum levels of IL-7, Bcell
      immaturity and decreased CD4+ T-cell counts was observed in patients with non-HIVrelated
      idiopathic CD4+ T-cell lymphocytopenia (ICL), which suggests that HIV-induced
      CD4+ T-cell lymphopenia (and not HIV viraemia itself) drives the expansion of immature transitional B cells in HIV-infected individuals50. So, as first reported several years ago27,
      there is evidence of an increase both in B-cell activation and in the frequency of immature B
      cells in HIV-infected individuals.


      Cd4+ t cell are killed by Hiv ,next
      B cell are afected , they became immature transitional b cells (they dont transform in memory b cell)

      If there is no memory b cell according to the "balck swan" theory there is no ebv
      This paper shows that cd4+ t cells are important for B cell maturation
      And hiv afects direct or indirect the t and the b cell populations


    • The anti-EBV action of AZT has nothing at all to do with HIV. Seems that you are getting blinded by the fact that AZT is primarily used on HIV patients.

      In the context of MS being perhaps driven by EBV, AZT is showing itself to be a potent anti-EBV agent. This is why it's used in non-Hodgkin's lymphoma, as it destroys the cancerous cells which are loaded with EBV.

      It's been discussed on this blog numerous times that there aren't any potent anti-EBV agents, which makes testing the EBV theories difficult. Well, here is an already existing agent that seems to be quite effective in targeting EBV.

      Forget about the fact that it was developed as a drug to treat HIV patients.

    • I have a diagnosis of SPMS, and have symptoms for over 25 years.

      I tried Raltegravir for a couple of weeks, and that did not appear to do anything for me.

      I am taking Valtrex, and that does not appear to do anything for me. Based off of a comment by Prof Pender in an interview, a number of years ago.

      On Monday I pick up my first dose of Combivir. FYI in Australia, it can be prescribed by a GP (no neuro needed), however, if its not for HIV, its not subsidised by the Govt (dont know if there are any generics available) and it is NOT cheap; i *think* its around $600 but not completely sure if thats for 60 or 120 tabs. Pick it up and pay for it on Monday and the chemists here in Aus get confused when medication is not subsidised by the Govt.

      Next week I am also speaking / interviewing to be considered for the ATA188 trial (ie for the allogeneic version of Penders treatment Its recruiting now

  • Vitamin D levels are not at their lowest in winter, they are at their lowest in March/April. You would expect the virus to trigger just as levels start to rise, like cold sores and sun exposure. So IF vitamin d affects the severity of Glandular Fever the effect would be seen in April.

    • EBV infected B cells, in lymphomas can produce effects far from the site of the lymphoma, so they may be no where near the brain. For example there is severe itching all over the body even though the lymphoma is very small and localised.

    • I keep an open mind given that infected memory B cells may only carry a few copies of EBV. But Pender,s hypothesis is surely infected B cells get zapped by CD8 T cells, I haven't brought T cells into my equation yet. But may do in the future.

      Are the B cells autoreactive…so far the evidence is weak. I currently think they are

  • A report from February 2018 supports the theory that EBV is the cause of RRMS, and probably most other autoimmune conditions.

    My theory is that, in an overzealous attempt to eradicate the EBV (or perhaps varicella), antibodies will target the viral signals coming from even the dormant viral particles hiding in neuronal cells, chewing through the myelin sheath like a black bear through a garbage bag in a misguided effort to sanitize the CSF.

    The CSF is a sterile environment with no means of immunomodulation, thus a faulty template becomes established for attacks against EBV in the rest of the body.

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