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Interesting study of mono/glandular fever that could be relevant to ME

Discussion in 'Other Health News and Research' started by Woolie, Dec 15, 2014.

  1. Woolie

    Woolie Gone now, hope to see you all again soon somewhere

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    I've posted some key sections below.

    Basically, the study suggests the severe symptoms in mono result not from an "abnormal" immune response, but rather from the high proportion of latently infected B cells at that time that are going into their lytic cycle (active replication) and subsequently dying.

    The idea is that in the early stages of mono symptoms, a huge number of B cells are doing this. Then fewer, then fewer still, till eventually the number is sufficiently low that you're asymptomatic.

    This is really different from the conventional account, which is that people with severe mono essentially "overreact" to the infection, mobilising too many T cells and expanding their numbers too fast.

    Now, imagine if some of these people manage to contain the initial lytic replciation, but still have a high viral load (lots of latently infected B cells). They might be fine till another infection comes along, which might provide a trigger towards more lytic replication. Then the cycle starts again, and again and so on... it starts to look like ME.

    Its relevant to ME because:
    * Early antiviral studies suggested that in some cases of ME, there might be a higher-than-normal proportion of B cells latently infected with EBV. But later researchers came to doubt this, because almost everyone carries EBV latently infected B cells, and they're not sick. So came the idea that its not the infection itself, but rather our abnormal immune response to it that causes the problem. This article suggests that the two might be linked after all.
    * It could be extended to any virus that has latent and lytic phases. Like enteroviruses? But the triggering factors could be different.

    I like it because:
    *Its never made sense to me what sustains our "abnormal immune response". I understand that an abnormal immune event might lead to others further down the line, but eventually, the effects would diminish, if only because T cells are being constantly replaced. A latent virus provides a mechanism for sustaining the process indefinitely.
    * There's a big danger that if the abnormal immune response account is wrong, then we might end up treating the reaction, not the problem. That could end up making things worse. So if there is a virus at the bottom of all this, we need to know.

    What I don't so much like about it:
    *Where is the evidence of lytic replication in ME? I suppose we might be largely succesfull at aborting the full relicaiton cycle (abortive replication, as Glaser and Lerner believe). But as @Butydoc points out, shouldn't we be able to detect some of the waste products of this kind of major event?
    *At best, it could surely only account for some cases.
    * The account they offer of multiple sclerosis seems dodgy - why would the byproducts of this war between the virus and the immune system predispose to autoimmunity? It seems more likely to me that the latently infected B cells have a more direct role here.

    Hadinoto, V., Shapiro, M., Greenough, T. C., Sullivan, J. L., Luzuriaga, K., & Thorley-Lawson, D. A. (2008). On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood, 111(3), 1420-1427.
    Our data show conclusively that by the time the clinical symptoms of AIM (actue infectious mononucleosis) arise, the level of mBLats (Memory B cells latently infected with Epstein-Barr virus) is always rapidly decreasing. Therefore, the emergence of clinical symptoms coincides with the massive cell death associated with the exponential decay of mBLats, not with infection per se. In this study, we have proposed that this death is associated with homeostatic culling by apoptosis, which in turn triggers entry into viral replication. It is conceivable therefore that the difference between asymptomatic primary EBV infection and AIM in adults is the extent to which the dying mBLats initiate viral replication. These ideas cast doubt on the findings of Silins et al28 who claimed that the main difference between symptomatic and asymptomatic primary EBV infection lies not in the levels of infected cells but in the extent to which T cells are mobilized and expanded. However, they measured viral loads at the peak of infection for asymptomatic patients (ie, the appearance of antiviral antibodies) but past the peak for AIM patients (ie, the time when clinical symptoms arise). Had they measured viral loads at the peak for AIM patients they would have found consistently higher viral loads than in the asymptomatic carriers.
    ….

    EBV infection and AIM in particular are risk factors for several important diseases, including Hodgkin disease8 and multiple sclerosis.5 It has also been suggested that AIM permanently impacts the immune system.4 We have proposed that AIM symptoms are coincidental with the rapid destruction by CTLIEs of mBLats as they enter into viral replication. Since up to 50% of mBLats are latently infected at the peak of infection and their half-life is approximately 7 days, this implies that 50% of mBLats, constituting 25% of the entire memory B-cell compartment, may be destroyed in 1 week at the height of the infection. This constitutes a massive, continuous deposition of cellular and viral antigens into the system. This action could be what is responsible for the long-term damage inflicted on the immune system and the predisposing factor for the AIM-associated diseases.

    We conclude that by the time AIM patients arrive at the clinic the immune response has already minimized the cycles of reactivation and infection of new B cells, leaving the high levels of mBLats in the blood to simply decay through reactivation of viral lytic replication until a low-level equilibrium is attained. This culling process may be initiated by the same processes that regulate the normal half-life of memory B cells.
     
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  2. Woolie

    Woolie Gone now, hope to see you all again soon somewhere

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    More about EBV and mono and its consequences, for those into this:

    The first two articles suggest that recent infection history can influence your immune reaction to EBV - or example, an episode of flu in the year preceding (not clear how long exactly) can cause something called T cell cross reactivity (T cells responding to the original virus cross react with those responding to the new EBV). It might explain the extreme immune reaction seen in mono, and why people are sicker if they encounter EBV in teens/adulthood than in childhood. They have more infectious history!

    But its not simply an exaggerated immune reaction it also seems to be an ineffective one. The third article shows that the risk of Hodgkin lymphoma (an EBV related cancer) is much much higher for people who’ve had mono than those who haven’t (even tho' most of them are also EBV positive, they just didn't have the full mono reaction). Suggests poorer control of EBV when accompanied by mono symptoms than when its asymptomatic.

    Clute, S. C. et al. Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis. J. Clin. Invest. 115, 3602–3612 (2005).

    Rouse, B. T., & Sehrawat, S. (2010). Immunity and immunopathology to viruses: what decides the outcome?. Nature Reviews Immunology, 10(7), 514-526.

    Hjalgrim, H., & Engels, E. A. (2008). Infectious aetiology of Hodgkin and non‐Hodgkin lymphomas: a review of the epidemiological evidence. Journal of internal medicine, 264(6).

    Curious fact from last study: both mono and Hodgkin lymphoma appear to be "middle class diseases". The higher your social class, the greater your risk! The explanation for this seems to be tied up with the hygiene hypothesis: the better your hygiene, the later in life you encounter EBV, and the greater your risk of complications.

    I wonder if ME patterns the same way.?


    Relevance to ME:
    I think it puts the latent virus hypothesis squarely back in the picture.
     
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  3. taniaaust1

    taniaaust1

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    Thanks I found that quite interesting the parts I could get my brain around. I had very severe mono when I was a teen.

    I really wish I could trial that drug which kills off the B cells as Ive always thought that one maybe could help me and this article further makes me wonder about that.
     
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  4. anciendaze

    anciendaze Senior Member

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    We have already seen that EBV has three latent states which do not necessarily lead to lytic replication. This conflicts with the common assumptions about the meaning of "latent". It does seem that EBV is capable of replicating DNA without lytic replication which kills cells and releases virions. I pointed out some time ago that this could enable the virus to exploit clonal expansion of infected host cells to increase numbers of infected cells enormously without increasing evidence of viral infection from lysis.

    In fact without lytic replication the only time cells would "spill their guts" would be when they died from old age. This fits perfectly with the observation that EBV is very good at immortalizing cells. This would make sense if the virus gains a substantial advantage from altered cell behavior. (This is neither my own wild idea, unsupported by evidence, nor exactly late-breaking news. Work on the connection between activity in the "latent" stages and immortalization has been around for quite a long time.)

    What this would weaken is the connection between numbers of infected cells and levels of antibodies to early antigens inside the nuclear membrane. I was already suspicious of the assumption of a linear relation between viral activity and antibody levels before the group in Berlin published their work. If one virus is able to manipulate antibody response to its advantage a lot of simplified hypotheses about testing for viral load fail.

    This has a direct relation to work on B-cell lymphomas and MS.

    To those who insist that EBV can't be "the cause" because "everybody is infected with EBV" I want to say that Nature never signed any agreement about making things simple. If all EBV strains were the same we might all die of Burkitt's lymphoma. Whether because of different strains, or because of different behaviors in different contexts, I think we now have enough evidence right now to search for subsets of infected cells with peculiar behavior. This can be much more specific than suppressing all immune response, or depleting large numbers of B-cells, which hasn't worked all that well in treatment. We should now be looking for a tiny percentage of infected cells expressing unusual epitopes.

    The success of adoptive immunotherapy in treating some lymphomas strongly supports the idea that treatment can be far more effective and far less damaging when it is appropriately selective.

    As a small side benefit from this view we would end the marginalization of patients with ME in a diagnostic and treatment ghetto unrelated to "real diseases". There is no question that being able to diagnose, treat and cure the life-threatening diseases mentioned above before they reach nearly hopeless late-stage pathologies would be a great medical advance.
     
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  5. Woolie

    Woolie Gone now, hope to see you all again soon somewhere

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    @taniaaust1, I'd like to try this drug too! I think the effects of rituximab may be due to depletion of EBV latently infected B cells. Jonathan Edwards thinks it works by inhibiting autoimunity, on the basis the people don't respond immediately to the drug. I'm not convinced by what he's said so far (but there may be more I just don't know).
     
  6. Woolie

    Woolie Gone now, hope to see you all again soon somewhere

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    @anciendaze, I'm pleased to hear from you. Have been following your posts.
    Yes, I expect without clonal expansion, we wouldn't be seeing any of these long-term consequences of EBV infection. The reservoir of latently infected Bcells would simply decline over time. Dying cells might attempt to lyse, but probably not successfully in someone with immunity. The net result would be a slow decline in latent infection - and symptoms - over time. (okay, maybe some crossinfection of B cells could occur, from the tonsillar compartment, there seems to be some evidence for that, but even so, I think viral loads would ultimately decline over time).

    Yes, I have seen much on this too, mainly from the oncology lit. A high load of latently infected B cells might lead to immune abnormalities in and of itself, even if there is minimal transition to lysis.

    The Berlin paper seems to me to support the hypothesis that the immune abnormalities seen in MECFS are the consequence of an ongoing immune response to EBV which exhausts CD4 and CD8 T cells, amongst others. But I think the patterns shown in this paper - depletion of cell reservoirs we know are important in managing acute IM - support that idea that its not just a high proportion of latently infected B cells that's the problem (they would not attract immune activity of this kind). There must be some considerable proportion attempting to lyse.

    Yes, EBV seems to be "the cause" of an increasing list of illnesses. True, not everyone gets these illnesses, so there must be virus-specific, situational and host factors that contribute too. But that doesn't undermine the cause. I think you might like the Rouse et al paper I listed above. It discusses some of these various factors.

    I've been carefully examining the literature for illnesses for which EBV - and more particularly IM - is a factor, and so far I have read convincing evidence that IM is a major risk factor for:
    - MS
    - Hodgkin lymhoma
    There seems to be involvement of EBV in SLE, RA, and Sjogrens syndrome too, but I haven't read enough yet to convince me the link is causal.

    Yes, I want this too! Klimas et al have mentioned this as a possibility.
     
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  7. Jon_Tradicionali

    Jon_Tradicionali Alone & Wandering

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    Zogor-Ndreaj, Shkodër, Albania
    http://dx.doi.org/10.1155/2012/189096

    CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

    Abstract
    CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV.
     
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  8. Iquitos

    Iquitos Senior Member

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    Can someone tell me what "development of ectopic lymphoid follicles in the target organ." means?
     
  9. melamine

    melamine Senior Member

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  10. Woolie

    Woolie Gone now, hope to see you all again soon somewhere

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    Thanks, @Jon_Tradicionali, fascinating! I've had a quick look over and will look forward to reading in detail later. Its a pretty well integrated account of how latent EBV infection could contribute to autoimmune diseases. The only part I'm not convinced of (so far!) is that a reduced CD8+ T cell response underlies it all. For two reasons. First we know the risk of MS is higher following symtpomatic mono than it is following asymptomatic EBV infection (people who are seropositive but never got mono). And we know that the risk of full mono increases with age of contact with EBV. So in other words, there are situational factors contributing to MS risk here as well (not just underlying, permanent immune abnormalities). We also know that mono is accompanied by a massive surge in CD8+ T cell numbers, amongst others. So it seems more logical to me that the CD8+ T cell depletion is a consequence of, not a cause of, the immune response to ongoing EBV infection.This is also how I read the results of this article (T cell exhaustion rather than deficiency to start with):

    www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085387#pone-0085387-g006
     
    MeSci likes this.
  11. anciendaze

    anciendaze Senior Member

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    Just want to caution people. When we talk about CD8+ T cell depletion, outside of therapies deliberately destroying them, we are talking about finding fewer in a particular physiological compartment, generally peripheral blood. This can be accompanied by increased numbers of CD8+ T cells in other places. This often happens when they go after a viral pathogen in those tissues. A drop in CD8+ T cells is fully consistent with other reports of finding CD8+ T cells in dorsal root ganglia, something which started me thinking along these lines years ago. Here's a review which might contribute useful information to the discussion.

    My point is that missing immune cells in one place may easily turn up in places you have not looked. There is a well-known example among herpes-type viruses. I've often wondered what doctors would think if this produced no convenient diagnostic signs when pain appeared years after initial infection.

    Added: There is one special issue with apparent depletion I meant to make clear, but did not. If immune cells themselves are infected, and that is causing damage to other tissues, this infection may not be apparent in studies based on peripheral blood for the simple reason that most of the abnormal cells are in those other tissues where you did not look. While there will always remain some in peripheral blood, which is their main means of transport, this kind of unsuspected activity is very likely to push the chemical signals from them below the threshold for detection.
     
    Last edited: Dec 18, 2014
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  12. anciendaze

    anciendaze Senior Member

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    Ectopic is general medical jargon for "out of place", as in ecotopic pregnancy. Follicle is Latin for a small cavity or sack. Lymphoid means related to the lymphatic system, where immune cells and the debris they generate are collected. This is also where things like B-cells, T-cells and dendritic cells meet to "talk shop" about what they have been doing recently.

    Putting this all together we have a small cavity or sack in a place you do not expect to see it filled with immune cells and debris they have collected. This is real evidence of either infection, cancer or an immune system which believes it is fighting an infection. Here's an example.
     
  13. melamine

    melamine Senior Member

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    @anciendaze - I am "liking" your posts even though I cannot claim to understand the intricacies of the articles. I think I get the general drift. o_O

    I posted a link above to a definition of ectopic lymphoid follicles, but you did a great job explaining it in more colloquial terms!

    p.s. - love the pygmy marmoset! Reminds me of baby bat images I was looking at the other day.
     
  14. natasa778

    natasa778 Senior Member

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    Could this fit with cases of (spontaneous, or minimal-intervention) ME remissions or recoveries? (assuming there are enough such cases to even begin to speculate...)
     
  15. halcyon

    halcyon Senior Member

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    I never realized there were different strains of EBV. I wonder if it would be worth looking for prevalence of certain strains (or certain combinations of strains, as in superinfection) in ME patients. It looks like EBV superinfection is common even in healthy individuals, but as you say it's not that simple.
     
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  16. anciendaze

    anciendaze Senior Member

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    Quite possible. I would classify this as either chronic or remitting-relapsing. If I was infected in childhood, (which matches reports of one outbreak I had never heard about until I read about it in 2010,) I could say I have repeatedly climbed out of long crashes, and functioned fairly well, though certainly not on a par with healthy friends, until the next crisis and crash. This is merely anecdotal, but I am not alone. I believe Gerwyn Morris has a similar history. You might also check with someone who has been following the disease since it became a public issue, like Paul Cheney, to see if they have recognized such a subset.
     
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  17. natasa778

    natasa778 Senior Member

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    Going on the recent MS-related research, there are indicators that the interplay between person's HERVs and exogenous EBV could be the key factor, where the inherited HERV polymophisms determine how the infection and/or disease play out. I don't have it to hand but there is a thread on this somewhere.
     
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  18. MeSci

    MeSci ME/CFS since 1995; activity level 6?

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    I'm fogged at the moment but couldn't see a link to the study , so did a search - here it is. This thread looks interesting but I will have to return to it when my brain is working!

    Meanwhile, I would be interested in @Jonathan Edwards's opinion on it and the theory.
     
  19. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I'm not quite sure what's new about this theory. It sounds pretty much like the explanation my mother gave to me when I had mono nearly fifty years ago. (At the time my mother ran the EBV research at the Central Public Health Laboratory in the UK.) Maybe things have gone around in a circle.

    I was not aware of strains of EBV. My understanding was that Burkitt lymphoma occurred in certain regions of Africa because of co-infections and malnitrition. But I have not looked at this for years. Dorothy Crawford, who worked with my mother in the 1970s and is now a leading EBV authority has recently written a book called 'Cancer Virus' that reviews all the history. It may well be of interest to people here. I am intending to read it but I have to borrow it from my mother and now that she is 93 I am not sure when she will have finished with it!

    EBV as a possible factor in all sorts of immune diseases has been researched with great enthusiasm almost from the moment it was discovered. In the end most of the stories ran to earth with no conclusion. It is still worth taking an interest in but as we all know 'the things you are lible to read (on PubMed) - they aint' necessarily so.
     
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  20. Sasha

    Sasha Fine, thank you

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    You can buy it from Amazon Marketplace for a bargain £7 including p&p...

    http://www.amazon.co.uk/Cancer-Viru...8&qid=1419009140&sr=8-1&keywords=cancer virus
     

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