A smoking gun?

A

The big hole in the EBV hypothesis of MS is how does the virus cause the disease at a molecular and immunological level. There are as many theories as thinkers. 

One theory is that EBV infects the CNS and MS is caused by an immune response to the virus in the brain of MSers. MS is then due to bystander damage of the immune cells finding and attacking the EBV infected cells. The evidence that EBV infects the brain is strengthening but is not an accepted fact.  In fact, it remains very controversial.

In the paper below from Francesca Aloisi’s laboratory, it shows that a large number of CD8 T-cells in the brains of MSers are EBV-specific targeting EBV proteins from both the latent and lytic phase of the EBV life-cycle. This is potentially a very important paper but needs to be reproduced. 

The big hole in the EBV-infected brain and CD8+ T-cell hypothesis is why do patients do so well on natalizumab and why does anti-CD20 therapy prevent rebound post-natalizumab? 

If the brain was infected with EBV and you blocked immune surveillance using natalizumab surely you could expect some ill-effects? We don’t see this happening clinically. In fact, we see the opposite; MSers on natalizumab have NEDA, a lot of them see an improvement in disability, they ‘normalise’ brain volume loss, they see a reversal of fatigue and/or sickness behaviour, etc. Surely natalizumab is the one experiment that argues against a direct CNS infection as being the cause of MS? Maybe not. Natalizumab may not stop smouldering MS which is the true disease and this may take many decades to manifest itself.

If MS is due to EBV-specific CD8+ cytotoxic T-lymphocytes attacking the brain of MSers, why does rituximab a drug that takes out predominantly B-cells and not CD8+ cells prevent rebound post-natalizumab? Some have argued that the B-cells are needed to travel to the brain to present antigen to the CD8+ T-cells. I don’t by this there are other professional antigen-presenting cells in the brains of MSers that can do this job. Others quote the new evidence that T-cells need help from B-cells to cross the blood-brain barrier. This does not explain why some of the carry-over PML cases from natalizumab to rituximab (or ocrelizumab) have developed IRIS (immune reconstitution inflammatory syndrome).  In the latter cases IRIS causing T-cells are trafficking to the brain in the absence of circulating B-cells.

So this paper generates more questions than it answers. It does demonstrate that we need to really find-out if EBV is driving MS from within the CNS or from its effects on the immune system in the periphery. These two scenarios require different treatment approaches. However, this should not stop us from exploring both approaches, often it is the experiment that disproves the hypothesis.

It looks as if October 2019 is going to be the month of EBV and MS. 

Serafini et al. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the multiple sclerosis brain and interact locally with virus-infected cells: a clue for a virus-driven immunopathological mechanism. J Virol 2019 (accepted manuscript) DOI: 10.1128/JVI.00980-19

ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). Yet, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS could stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique.

Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus, influenza A virus) proteins and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a-positive, suggesting a cytotoxic phenotype, and stuck to EBV infected cells.

Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV may contribute to inflammation causing CNS injury.

IMPORTANCE: EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS and immune reactivity toward EBV is higher in persons with MS indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS might stimulate an immunopathological response causing bystander neural cell damage. To verify this, we need to identify the immune “culprits” responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

18 comments

  • In this cluedo the killers can be two and not one, so this is why the footprints dont exactly match… This is how all the good crimes are orchestrated.
    I know I am a bore, but EBV+HERV maybe fill the pieces of the puzzle.

  • Mult Scler. 2016 Mar;22(3):279-91. doi: 10.1177/1352458515588581. Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins. van Nierop GP, Mautner J, Mitterreiter JG, Hintzen RQ, Verjans GM.

  • “it shows that a large number of CD8 T-cells in the brains of MSers are EBV-specific targeting EBV proteins from both the latent and lytic phase of the EBV life-cyc”

    So those patients that have this response are all fine (t cell in the brain are good, and doing a good job)

    Acording to this

    One way of targeting EBV is via immunotherapy and Michael Pender, from Brisbane, has been promoting this strategy for over a decade. His data on using autologous ant-EBV CTLs (cytotoxic T-lymphocytes) is impressive

    https://multiple-sclerosis-research.org/2019/09/black-swan-2/#comment-65754

    Like Md says manny manny times

    You cant have it both ways

    🙂

  • Also natalizumab take the t and b cell out of the cns and this makes ms better

    Michael pender puts the t cells in the brain and this makes ms beter

    Again you cant have it both ways

    🙁

  • Can someone explain why if the virus and the immune cells are in the brain, and an autoimmune/ virus attack starts why does it not affect all the brain, why is it limited to smallish regions?

    And last month I seem to remember you showing the lesions are often associated with veins. Does that insinuate something leaking in from outside? Or am I misunderstanding?

  • Maven Muraro as this to say

    Growing evidence points to a deregulated response to Epstein–Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8+ T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD‐1) and human inhibitor receptor immunoglobulin‐like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8+ CD57+ T cells are able to kill EBV‐infected cells in healthy donors. In contrast, an anergic exhaustion‐like phenotype of CD8+ CD57+ T cells with high expression of PD‐1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8+ CD57+ T cells in meningeal inflammatory infiltrates from post‐mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

    Programmed death 1 is highly expressed on CD8+CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

    It is plausible to suggest that the inability of
    CD8+ CD57+ T cells to clear EBV infection in the CNS
    enables the persistence of chronic inflammation that
    underlies the observed more rapid progression of MS.
    However, we cannot rule out that the CD8+ CD57+ T
    cells’ involvement in the disease process, documented by
    their detection in MS brain tissue, could be secondary to
    other inflammatory events occurring in the MS process
    and that the cells may play a disease-countering role,
    potentially through immune regulatory mechanisms, as
    we suggested in one previous report.

    Our results suggest that
    the inability of cytotoxic T cells to control EBV replication
    during inactive MS could set the stage for viral reactivation
    in the CNS and for disease progression

    Pender hypothesis?

    doi:10.1111/imm.12808

    Natalizumab doesnt fit in thos scenario

  • What weight might be given to a newer discovery of targeting Rogue helper T cells and the protein on their surface called CXC R6 recently found by scientists at Boston Children’s Hospital Boston Massachusetts. Supposedly targeting this protein may ameliorate or reverse multiple sclerosis, at least the forms that have inflammation, according to senior investigator Eileen Ramold-O’Donnell Ph.D., of the hospital’s program in cellular and molecular medicine. If this turns out to be valid, would it tie in with the Epstein-Barr hypothesis?

  • Re Natalizumab may not stop smouldering MS which is the true disease and this may take many decades to manifest itself

    Isn’t decades too long?
    If patients were smouldering with natalizumab, it should have/would have been manifest by now
    As has been the case with rituximab/ocrelizumab

  • Why is there no data from a population of normal controls? or even diseased but not-MS control? What is the prevalence of these cells like in the CNS of the normal population?

    I appreciate a comparison of CMV reactivity within these PwMS but the data seems to indicate an apparent increase vs CMV-specific T cells, but nothing of PwMS over the general population.

    Or am I missing something?

  • In reviewing literature, I found 30 articles linking between EBV and MS in the 1970s but here we are almost 50 years later still discussing this.

    In this time, there is no vaccine on the market, no antiviral treatment of EBV with a bout of mononucleosis/glandular fever and no antiviral treatment of EBV in MS other than the phase 2 trials of Dr. Pender.

    This should give little reassurance to any MS patient to be optimistic with the current state of the MS research world.

By Prof G

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