Friday, 21 April 2017

MS and EBV

If EBV is the driver of MS, then there must surely be evidence that something related to EBV that associates with disease activity.

Does the Black Swan get it?

Gieß RM, Pfuhl C, Behrens JR, Rasche L, Freitag E, Khalighy N, Otto C, Wuerfel J, Brandt AU, Hofmann J, Eberspächer B, Bellmann-Strobl J, Paul F, Ruprecht K. Epstein-Barr virus antibodies in serum and DNA load in saliva are not associated with radiological or clinical disease activity in patients with early multiple sclerosis. PLoS One. 7;12(4):e0175279.

OBJECTIVE:

To investigate the association of Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) immunoglobulin (Ig)G antibodies in serum as well as EBV DNA load in saliva with radiological and clinical disease activity in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS).

METHODS:

EBNA-1 and VCA immunoglobulin (Ig)G antibodies were determined in serum of 100 patients with CIS/early RRMS and 60 healthy controls. EBV DNA load was measured in saliva of 48 patients and 50 controls. Patients underwent clinical assessment with the Expanded Disability Status Scale (EDSS) and 3 Tesla magnetic resonance imaging at baseline and after a median of 20 months of follow-up (n = 63 for MRI, n = 71 for EDSS). The association of EBV parameters with occurrence of a second relapse, indicating conversion to clinically definite MS (CDMS), was evaluated over a median of 35 months of follow-up after the first clinical event (n = 89).

RESULTS:

EBNA-1 IgG antibody frequency (p = 0.00005) and EBNA-1 and VCA IgG antibody levels (p<0.0001 for both) were higher in patients than in controls. EBV DNA load in saliva did not differ between groups. Neither EBV antibody levels nor DNA load in saliva were associated with baseline or follow-up number or volume of T2-weighted (T2w) or contrast enhancing lesions, number of Barkhof criteria or the EDSS, or with the number of new T2w lesions, T2w lesion volume change or EDSS change on follow-up. Likewise, levels of EBV IgG antibodies in serum and DNA load in saliva were not associated with conversion to CDMS.

CONCLUSIONS:

While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease.

Sisay S, Lopez-Lozano L, Mickunas M, Quiroga-Fernández A, Palace J, Warnes G, Lafuente RA, Dua P, Meier UC. Untreated relapsing remitting multiple sclerosis patients show antibody production against latent Epstein Barr Virus (EBV) antigens mainly in the periphery and innate immune IL-8 responses preferentially in the CNS. J Neuroimmunol. 2017 May 15;306:40-45.

BACKGROUND:Multiple sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS). Reliable biomarkers are urgently needed for its diagnosis and management, and as clues to its pathogenesis, in which EBV is implicated.
OBJECTIVE:To measure IgG antibodies against EBV nuclear antigen-1 (EBNA-1) and innate inflammation status in paired serum and cerebrospinal fluid (CSF) samples from untreated relapsing-remitting MS (RRMS) patients.
MATERIALS AND METHODS:Anti-EBNA-1 IgG titres and IL-8, IL-1β, IL-6, IL-10, TNF-α and IL-12p70 cytokine levels were measured in 20 untreated RRMS-patients and 17 healthy controls.
RESULTS:We found higher serum anti-EBNA-1 IgG and IL-8 levels in RRMS-patients than in healthy controls. Interestingly, levels of IL-8 - relative to total protein - were much higher in the CSF, whereas the anti-EBNA-1 antibodies were significantly higher in the sera. More detailed analysis showed that anti-EBNA-1 antibodies relative to total IgG were also higher in the serum in the majority of RRMS patients compared to CSF. Levels of anti-EBNA-1 IgG and IL-8 showed a strong correlation between serum and CSF.
CONCLUSION:These findings in newly diagnosed RRMS-patients imply anti-EBNA-1 antibody production mainly in the periphery and innate immune responses preferentially in the CNS. Both their potential as disease biomarkers and their implications for the pathogenesis of MS warrant further investigation.

So both studies agree that there is evidence of EBV infection in people diagnosed with MS. So the Black swan lives. 

However, no evidence of viral shedding in saliva and clinical activity was found, but not sure why this would be the casse even if EBV was the driver for attacks.

15 comments:

  1. If only there were some way to dramatically decrease EBV viral load from the human body to see whether or not this reduction has an impact on MS.

    Oh, wait, there is! Since EBV takes up residence in B cells when in its inactive state, both Rituxan and Ocrevus effectively rid the body of much of the Epstein-Barr virus, since they wipe out a majority of B cell types. In fact, Rituxan is the only drug FDA approved as an anti-Epstein-Barr agent, for use in people having undergone organ transplants.

    And, HSCT also wipes out EBV in the human body as it decimates the entire immune system as a first step in the treatment protocol.

    Isn't it something that all three of these treatments are among the most effective in tamping down MS? Could it be that researchers are not seeing the forest for the trees, or, more correctly, in this case not seeing the trees for the forest?

    While massive amounts of money and manpower continue to go into research on newer and more sophisticated ways to profoundly alter the workings of the human immune system, a highly evolved mechanism whose tinkering with nobody quite knows the long-term effects of, hardly any effort is being made to find an effective anti-EBV agent.

    I also noticed that GeNeuro is now testing their MSRV targeted monoclonal antibody on diabetes type I in addition to ms. Could it be that EBV is up regulating MSRV, thus causing the body's own cells to produce proteins identifying those cells as invaders. An elegant explanation of autoimmunity, from this layman's point of view.

    So, if we were to eradicate EBV from the bodies of patients experiencing a wide range of so-called "autoimmune" diseases, would we see a resolution to those diseases?

    Personally, I can't think of a more important question…

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    1. A number of years; when my friends and I were saying good night outside Nat Sherman's (42 & 5 th) 7 pm ish we would regularly have to jump out of the way of a man in a motorized wheelchair- was that you?

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    2. At AAN they are presenting a new phase I trial result about EBV and MS
      https://www.aan.com/PressRoom/Home/PressRelease/1547

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    3. We know that Dr Pender is doing a breaking news presentation, once the abstract we can have a greater look and maybe NDG can cover it.

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    4. Aidan, though in theory that very well could have been me, in practice I don't think I regularly zoomed around 42nd St. and Fifth Avenue. Generally try to stay away from the Times Square area, way too many tourists for my liking… These days not doing all that much zooming, as the disease has taken it's toll.

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    5. I have been tackling ebv and it's may and varied effects on my body for the last 10 months, I'm just a person with ebv and I 100% wholeheartedly agree with your comment "if we were to eridicate ebv from the body....". From experiencing this virus as a 43 year old and the array of effects on the body that my doctors don't know what could be the cause or think are all in my head I do worry of the long term effects ebv may cause. If I could have this virus eradicated today I'm sure I wouldn't be first in line.

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  2. Once infected, forever infected... so I do not think reactivation would have anything to do with more MS activity.
    But I wonder, MD, if anybody looked at the EBV virus types in different populations in relation to MS. Because some populations, even though they get EBV, do not seem to get MS quite as often as Caucasians. And why is that? Is it all about HLA type?

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    1. Once infected, forever infected is not quite right. Eliminating B cells tremendously depletes EBV viral load in the human body. HSCT effectively rids the body of EBV.

      If we look at patterns of disease activity resumption in HSCT patients, we find that between years 10-15 after treatment the majority of patients see a resumption in MS activity. Is it out of the realm of possibility that this is because they get reinfected with EBV, which, after a number of years, causes a reactivation of the disease process?

      These time frames match well with what is seen in the general population. Folks get infected with EBV in their teenage/early adult years, and MS manifests some 10+ years after in genetically predisposed people.

      Not saying this is a slamdunk, but certainly worthy of further investigation…

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    2. Reinfection may be possible yes. Exchange of or contact with the saliva of another person also infected with EBV, for example. Couples may have EBV infection in both individuals.
      And probably the damage, the neurological lesions caused by MS will continue to trigger neurodegeneration, regardless of the treatment, because this process was already triggered there at the beginning of the disease, the interesting thing would be to have neuroprotective treatments concomitantly and to prevent oxidative stress.

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  3. Further, Rituxamab has proven to be very effective in clearing EBV in patients presenting with very high EBV loads post HSCT treatment for blood cancers…

    http://www.nature.com/bmt/journal/v31/n11/full/1704061a.html

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    1. I have that paper...nice job have read it. However i think in that case they do it with atg ,which leave some infected b cells behind that need to be clear because Ebv overload and they adressing PTLD risk

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    2. Here is how Prof. Pender's team does it:

      "EBV-specific adoptive immunotherapy involves growing T cells from the blood in the laboratory with an EBV vaccine to retrain the cells to be potent killers and then returning them to the patient by intravenous infusion. This treatment was developed by Professor Rajiv Khanna of the QIMR Berghofer Medical Research Institute in Brisbane to treat patients with EBV-related malignancy and does not require the use of any drugs. Professor Khanna and his team have successfully used this therapy to treat EBV-related metastatic nasopharyngeal carcinoma. This EBV vaccine expresses parts of three EBV proteins, which are crucial in allowing EBV-infected B cells to multiply and mature into memory B cells and plasma cells capable of producing large amounts of antibody."

      http://multiple-sclerosis-research.blogspot.com/2014/02/guest-post-professor-michael-pender.html

      The first patient to get this anti-EBV T cell therapy:

      "I have a very nerdy indicator of the improvements: Prior to 2007 I could score up to 97 planes landed in the iPad game Flight Control. After 2007 I gave up playing because I couldn’t land more than 14. Two weeks after starting the treatment I got 117. In May last year I landed 561!"

      http://patienttalk.org/killer-t-cells-a-new-way-to-fight-multiple-sclerosis-read-our-interview-with-gary-allen-one-of-the-test-subjects-for-prof-michael-pender-ms-research/

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  4. All this related to EBV, as it happens in the pathogenesis of this virus intrigues me a lot. What the hell happens to this virus that it can not be detected right, something like "we got it"? Looks like the same thing happens to the lymphomas caused by him, right? It seems that it appears and then leaves only a few clues, the traces it deletes...

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    1. ""The
      EBV-infected memory B cell exits from the germinal centre and
      circulates in the blood; it expresses no viral proteins except during cell
      mitosis"""""""The
      absence of viral protein expression allows the virus to persist as a latent
      infection in memory B cells despite a healthy immune response

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