Myelin Autoimmunity in T cells. Time to say schtop!. MS lesions are EBV killing zones

van Nierop GP, van Luijn MM, Michels SS, Melief MJ, Janssen M, Langerak AW, Ouwendijk WJD, Hintzen RQ, Verjans GMGM. Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients.  Acta Neuropathol. 2017 doi: 10.1007/s00401-017-1744-4. [Epub ahead of print]

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WM L) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry.

T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WM Lesion. WM Lesion-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed.

The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WM Lesions of the same MS patient, but not between paired NAWM and WM Lesion. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WM Lesions-derived TCL towards autologous Epstein-Barr virus (EBV) infected B cells (autoBLCL).

Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients.

What does this study suggest? 

Advanced Disease is associated with active inflammatory lesions, so maybe not too late for a DMT.

Is it time for the card-carrying  CD4 T cell immunologists to pack up their bags and work on a different condition.

Is it time to say no more CD4, Th17 immunology in lab mice.

There is no autoimmunity to myelin basic protein or myelin oligodendrocyte glycoprotein, Kir 4.1 (potassium channel)

Cells in active lesions recognized Epstein Barr Virus, cells in normal appearing white matter did not.

You don’t want your therapeutic drug to increase CD45RO, CCR7- effector memory cells..

The data suggests that CD8 T cells cause the active lesions or are associated with the active lesions and they are killing EBV infected B cells.

How does this fit with the B memory cell idea. It fits perfectly. 
If you get rid of the B memory cells you get rid of the EBV, so nothing to get the CD8 T cells going. It may suggest that blocking CD8 would stop the attack, but it wouldn’t remove the problem.

This supports the approach developed by Prof Pender in Oz…
What ever happened to ProfGs hope to be involved with this?

Why MS?

It maybe has something to do with the formation of the B cell follicles creating a steady stream of CNS B cells ripe for attack, if you get follicles in the joint you get arthritis.

However do we find T cell reactivity to EBV because we are looking for reactivity to EBV

Nice study from our mates in the Netherlands

About the author



  • [Rapturous applause]

    Hoorah! Something that positively rings with sense!

    Pender is on the right road.

    The black swan is surely something to do with EBV.

  • When I was at Uni in the early 1980s my friend developed Bells Palsy. I went to the neuro with my friend who was asked about her medical history. My friend mentioned that she had Glandular Fever aged 15 and I remember the neuro saying that Glandular Fever / EBV can lead to the development of MS! Why has it taken 35 years to start producing the evidence to actually show that EBV is the cause of MS? There is "slow", "bloody slow", and "neuro-immunology slow". Thank God for Prof P.

    • I presented my doctorate thesis (June 8 1982) on the subject because I observed acute viral infection in the past in MS patients before an accurate diagnose was done. I did skin tests in 1976 upon requests, the results were weird I decided to explain this observation and it started to be the base of my research : to identify the different populations of Lymphocytes in MS , I am Claude Martin,the author in the Lancet 1980 paper, my publication are Martin, Martin-Mondiere or Mondiere for my patent. I was young and they took over my research, without carry on my results, when Pr. Waksman presented me as the only one presenting a new light in MS. jealousy became high not only in France. I changed the treatment by stopping the aggressive treatment blocking the people to respond to viral aggression by producing the cascade of scavenger effects to avoid new relapse. When I presented the discrepancy on relapse with destruction of myelin and electric pain, results of inflammation, people commented about my perfect pink suit, my mother wanted me to wear as a real woman, really scientific. MS is reversible as I demonstrated decades ago before I refused to be high paid to inject "criminal treatment" to become a star in MS. Yes in 1982 I was ready to explain EBV and more. Today I still can explain to prevent MS with a nutrition plan, but I have no more an audience in MS.The explanation of my observations is controlled from studies as this one. I hope I will have the possibility to share my work one day for the interest of public health and all these young people handicapped without knowing why.

  • Would it not have been extraordinary if CD8+ T cells had shown no reactivity to EBV+ cell lines? Nearly all of us are chronically 'infected with EBV and require T cell control throughout life. Control INFLAMMATORY tissue (not employed) would almost certainly have shown T cell EBV reactivity.
    I recently suggested that the lack of any sort of demyelination in patients with frank EBV caused CNS conditions, such as meningitis and encephalitis was worthy of some consideration.I also hoped for some comment on the recently published paper (Dobson R et al EBV-Negative MS: a true phenomenon?) in which after uncontrolled and somewhat desperate efforts to make routinely sero-tested EBV negative MS cases into 'positives' came to the conclusion that 'it is possible to be truly EBV seronegative and develop MS'.
    Are these comments too embarrassing to discuss?

    • Say your bit, you have a platform. I'm not embarassed. I'll stick Dr.Ruths paper up tomorrow, but it is ProfGs interest not mine, I know nothing about EBV, I made no link of the oligodendrocyte either what about HERVS and said if you look for something you find it

    • "Would it not have been extraordinary if CD8+ T cells had shown no reactivity to EBV+ cell lines?"

      "all the patients had very low T cell reactivity to Epstein-Barr — about 0.1%. "This changed to up to 48% after the T cells were multiplied with the Epstein-Barr fragments. Importantly, the patients who have shown the most clinical improvement were the ones whose T cells showed the highest reactivity to Epstein-Barr virus after their incubation."

      The patient who got Tcells w/ 48% EBV reactivity had 16 years of spasticity,knee jerks, and limb weakness resolve along with sensory improvements. Walking distance went from 100 yards to 1 mile (see below interview at 15:00 mark)

  • "If you get rid of the B memory cells you get rid of the EBV"

    It seems that B memory cells hold the list of the "usual suspects", the antibodies against all pathogens that one's immune system has encountered up to now. Each one has her/his own unique list, but there is certain overlap between lists of different people, since we all get exposed to rather similar sets of pathogens.

    When CNS damage is detected, immune cells rush to the site of damage and try to identify the identity of the "criminal". To do so, they scan the list of "usual suspects" and therefore create antibodies against everything in that list. Since EBV is a common pathogen, it is usually in that list, so antibodies against it are usually detected in lesion site.

    What is more, this unique list of "usual suspects" leaves a trace in the CSF, the OCBs. These OCBs are unique, but overlap between different MS cases, as they reflect the list, as well as the protein pool of damaged CNS cells. No pattern is ever to be found in OCBs. They signal one thing only: there is some damage in CNS.

  • Therefore, depletion of B memory cells equals deletion of the suspects list. With an empty list of suspects, when damage strikes, the immune system is unable to make any arrest and enjoys the silence of the lesion site.

    This is the state you call NEDA.

  • Black swan idea look very elegant
    However in this study there is no cd8 t cells, no Bcell, no plasma cell in the brain ,so was your theory suggests no ebv…
    Still there is disease activity

    The present study analyses autopsymaterial fromfivemultiple sclerosis patients who received autologous stem
    cell transplantation. A total of 53 white matter lesions were investigated using routine and immunohistochemical
    stainings to characterize the demyelinating activity, inflammatory infiltrates, acutely damaged axons and
    macrophages/microglial cells.We found evidence for ongoing active demyelination in all of the five patients.The
    inflammatory infiltrate within the lesions showed only very fewT cells and CD8þ cytotoxicT cells dominated
    theT cell population. B cells and plasma cells were completely absent fromthe lesions.High numbers of acutely
    damaged axons were found in active lesion areas. Tissue injury was associated with activated macrophages/
    microglial cells.The present results indicate that ongoing demyelination and axonal degeneration exist despite
    pronounced immunosuppression.Our data parallel results from some of the clinical phase I/II studies showing
    continued clinical disease progression in multiple sclerosis patients with high expanded disability system scores
    despite autologous stem cell transplantation.

By MouseDoctor



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