Friday, 15 September 2017

#ResearchNews: could the Prineas lesion be due to a virus?

Challenging the dogma is something we need to do more often, or not? ;-)  #ResearchNews

Summary: This post describes the pathology of the very early MS lesion now known as the Prineas lesion. In these lesions, there is a massive death of myelin producing cells, called oligodendrocytes, by a process of programmed cell death. The death of these cells appears to occur before T and B cells have arrived in the lesion. What is killing these cells? Does this study slay the dogma that MS is an autoimmune disease? 

We have recently been criticised for not covering pathology papers on the blog. Apologies, I agree this is an oversight from our side. None of us are card-carrying pathologists; DrK has the most experience and runs a research group looking at MRI-pathology correlations. Dr Love (who we need to get to do some more writing for us) works in the brain bank at the Free University of Amsterdam and has published extensively on MS pathology. Then we have Mouse Doctor 1 and Mouse Doctor 2 (Thing 1 and Thing 2); they are very good at doing EAE pathology and are also very good at spotting bad research, dodgy data and its over interpretation. 




One of the most important studies in the field of MS pathology was published in 2004 describing the hyperacute MS lesion, which has subsequently become known as the Prineas lesion after the senior author of the paper, John Prineas, an MS pathologist based in Sydney, Australia. Professor Prineas has made many several seminal observations in MS and is one of my MS heroes. 

This Barnette-Prineas paper really challenges our understanding of MS and challenges the dogma. They describe the pathological postmortem findings in 12 patients with RRMS who died during or shortly after the onset of a relapse. Changes not previously associated with the formation of new symptomatic lesions were observed in 7 cases, i.e. extensive death of oligodendrocytes (the cells that produce myelin) by a cellular process called programmed cell death or apoptosis*, and the extensive activation of another population of resident inflammatory cells called microglia (tissue scavengers). 

The most remarkable observation was that there were very few or no lymphocytes in these lesions. Lymphocytes are the cells that are thought to drive autoimmunity and enter the brain and spinal cord from the peripheral blood. 

If these lesions don't have T & B cells in then what is causing the death of the oligodendrocytes? 

Prior to this paper it was believed that the first events in new MS lesion formation were orchestrated by lymphocytes. This dogma arose from observations in the animal model of MS called EAE (experimental allergic encephalomyelitis); it is now very clear that MS is not EAE. 




The famous 17-hour lesion above, is visible in the critical part of the brain called the medulla; the part of the brain that controls vital functions like breathing. The reduction in myelin in the lesion on the left appears pale, or almost white. Compare this to right side where the normal myelin stains blue. In the high-power picture below we see the myelin producing cells, oligodendrocytes, showing the characteristic signs of programmed cell death or apoptosis. There is a lack of lymphocytes in this area of the lesion. 



What is killing these oligodendrocytes? Could it be a virus? Is the influx of lymphocytes that are seen in older MS lesions a secondary response to the inciting agent? Too many questions and not enough answers. This paper challenged, and continues to challenge, current dogma and raises serious questions about the hypothesis that MS is an autoimmune disease. I for one don't believe MS is a primary autoimmune disease; I prefer the viral hypothesis and that the inflammation we see in MS is a secondary response to a virus. This paper has been very controversial and the world's pathologists still can't agree on the interpretation of the findings. The paper has been criticised by some very eminent pathologists, whereas other have kept a very low profile and not openly expressed an opinion. Why?


* apoptosis /ap·op·to·sis/ (ap″op-to´sis) a pattern of cell death affecting single cells, marked by shrinkage of the cell, condensation of chromatin, and fragmentation of the cell into membrane-bound bodies that are eliminated by phagocytosis. Often used synonymously with programmed cell death. apoptot´ic


Barnett & Prineas. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004 Apr;55(4):458-68.

The study describes the clinical and pathological findings in 12 patients with relapsing and remitting multiple sclerosis, who died during or shortly after the onset of a relapse. Pathological changes not previously associated with the formation of new symptomatic lesions were observed in seven cases, namely, extensive oligodendrocyte apoptosis and microglial activation in myelinated tissue containing few or no lymphocytes or myelin phagocytes. No current laboratory model of multiple sclerosis, in particular, experimental allergic encephalomyelitis, is known with these features, which raises the possibility of some novel process underlying new lesion formation in multiple sclerosis.

29 comments:

  1. There are a bunch of post mortem studies showing continued disseminated demyelination even in patients who underwent allogenic and autologous myeloblative HSCT.

    But it still cannot be denied that HSCT works incredibly well. Does this not show that the immune system is the main enemy?

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    Replies
    1. Absolutely not. The immune action is manifested as inflammation, that is swelling. Swelling in a closed compartment as the skull and the vertebral column exerts pressure to axons within the lesion site. Axons under pressure are not behaving normally -> relapse.

      Myelin destruction is taking place within lesions, therefore axons maintain their abnormal behavior -> disability.

      Delete
    2. Except HSCT substantially reduces disability accumulation (>50%); it does not just end relapses.


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    3. Please cite your references so that i can take a look.

      In any case, i should say that trials of any kind last for a few years, so they don't really catch permanent disability. They rather impact on short term disability, the inflammation related one.

      Delete
  2. What else is Prineas famous for? Can you get him to do a guest post?

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    Replies
    1. He did.
      https://multiple-sclerosis-research.blogspot.com/2011/12/guest-post-john-prineas.html

      Delete
    2. "He did"

      All he did was give CCSVI a downvote..how about his views
      now looking back at paper from 2004.

      Delete
    3. He has made his point with the paper. In the days of slides he presented at a meeting I organised. We had to advance the slides as we didn't have the technology set up to have this co-ordinated. The slides went horribly out of synch. However he still had 35 slides in each carousel (slide holder) when his 30 minutes were up

      Delete
  3. If MS is due to a virus attacking oligodendrocytes can you explain how natalizumab works?

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    Replies
    1. Stops response from the immune system.

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    2. Natalizumab, as Aidan said, like Fingolimod, disrupt the passage of lymphocytes into the CNS.
      The question is: why did these drugs not cure MS, since in theory the immune attack would be the cause of the disease?

      Delete
    3. Anon 2017. This is a good point.
      People who unfortunately die whilst taking natalizumab should be gold dust in explaining whats going on.

      If the immune response is controlling a virus, then the brain should be full of the offender.

      How ever we know of case where someone died of PML but the areas of MS had remyelinated, saying that removing the inflammation has allowed the body to repair. But was this an exception compared to the norm.

      Delete
  4. 'Prior to this paper it was believed that the first events in new lesion formation were orchestrated by lymphocytes'
    Some 7 years before the Prineas paper Gay et al provided extensive new quantitative evidence ( Brain 1997;120:1461) identifying the primary MS lesion using uniquely early tissues. A further more detailed analysis of 'pre-demyelinating' lesions was published in 2006 (Gay F, Clin Neurol Surg 108;324, confirming that the initial events in the CNS parenchyma were prior to the breakdown of the Blood-Brain Barrier and before any significant T cell infiltration. However, there was (as Prineas described) microglial activation, and of crucial importance, IgG/C3 complexes fixed to these activated cells. It was also noted that in these tissues the adjacent perivascular (V/R) spaces were replete with inflammatory cuffs, showing fully developed immune processes indicating antigen processing. (Esiri and Gay, J Neurosci 1990; 100:3).
    Further to these investigations in 2013 the activated microglia were found to be processing (pinocytosis) a Staphylococcal transportable toxin (Gay Mult Scler Rel Dis 20132;213) which was also detected within the immune complexes. The toxin was identified using Mass Spectrometry as Sphingomyelinase, which specifically induces Oligodendrocyte apoptosis . (Jana and Pahan, J Neuropharm 2007;2:184.
    The hypothesis is that the CNS has incorporated the lymphatic drainage of the adjacent nasopharynx, so that the MS CNS becomes an active processor of a variety of bacterial products, some of which induce inflammatory and degenerative lesions.
    These results need to be further explored.

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  5. Professor Prineas may be your hero, but this paper was published 13 years ago and has not helped one person with MS i.e. no treatments. I remember that around the same time an MS pathologists published a paper saying that there were four types of lesions - this caused a lot of hype at the time but came to nothing. If MS pathologists and EAEologists had been on the Titanic, it would have made no difference to the lives of MSers. The world of MS academics is a job creation scheme for those academics who couldn't cut the mustard. It's a backwater where 60s and 70s rejects can churn out meaningless papers and undertake meaningless research, while wearing their flared jeans and listening to Prog Rock (while injecting thin bleach into the brains of Roland Rat's chums). At least 50% of Prof G's time (clinical stuff) is of value. As bad as MS researchers are, MND researchers go down as the pits. They must thank their lucky stars they don't work in a payment on results basis.

    ReplyDelete
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    1. As for MND the "Ice Bucket Challenge" for ALS gave the social media fanatics a jolly.

      Delete
    2. Surely this world would be a much better place if everyone showed more kindness to each other - life is too precious to waste time making hostile comments. I am so grateful to all the team at Barts for the helpful posts on this blog.

      Delete
    3. @anon 3:11:00 sometimes harsh comments are necessary. Not all criticism is detrimental.

      Delete
  6. If Ms is not primary autoimmune disease

    Could you explain why Hiv infected patients dont get Ms?

    Obrigado

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    1. I've heard of a couple of people who have both HIV and MS. May be it's more less likely to get rather than don't get.

      Delete
    2. Here in Brazil I personally know a case of pwMS with HIV. She was first diagnosed with HIV, years later with MS.

      She lives in another state, contracted HIV from her ex-husband.

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  7. Professor GG, could you elaborate on the evidence that point to a viral cause of the 17-hour lesion? You haven't provided any so far.

    The following paper reviews viral causes of white matter lesions. None, including EBV, have any resemblance to MS lesions, neither in form, nor in topology. Can you provide a viral explanation of Dawson's fingers that are exclusively seen in MS?
    https://www.researchgate.net/publication/260444552_Viral_Infections_and_White_Matter_Lesions

    Can you provide any example of early MS lesion where virus action is evident?

    ReplyDelete
  8. Ultrastructural evidence for oligodendrocyte-based
    demyelination in MS lesions was suggested by Rodriguez
    and Scheithauer,19 who described early changes in
    the periaxonal oligodendrocyte processes, consistent
    with a “dying back oligodendrogliopathy.” Experimentally,
    these peculiar alterations of oligodendrocyte processes
    have previously been described in conditions of
    toxic oligodendrocyte damage38 and in the course of
    virus-induced inflammatory demyelinating diseases.39
    Similarly, the observation of dying-back oligodendrogliopathy
    in animals with a genetic deletion of MAG40
    indicates that selective loss of MAG and degeneration
    of distal oligodendrocyte processes are closely associated.
    All these data suggest that in MS patients with
    pattern III lesions, demyelination is induced by a functional
    disturbance of oligodendrocytes, possibly as a result
    of infection with a hitherto unknown virus or
    damage mediated by some unknown toxin.
    Most patients showing pattern III lesions had a clinical
    course of less than 8 weeks before biopsy or autopsy.
    However, patients with pattern III lesions in a
    biopsy taken within the first weeks after disease onset
    later developed a disease clinically and radiologically
    consistent with clinically definite relapsing-remitting
    MS.4
    Ann Neurol 2000;47:707–717

    ReplyDelete
  9. "..could you elaborate on the evidence that point to a viral cause of the 17-hour lesion?"

    Why are you so concerned with 17 hour lesions? What about decades long lesions? So far the only treatment to remove lesions is based on
    EBV CTL cancer therapies..Remove EBV and lessions vanish from MRI.
    ...So make of that what you will.

    These 17 hour lesions from RR patients who died from relapse seems a very rare case..so rare what can you deduce?..that it's not MS?

    "However, recent neuropathologic findings have shown that pathologic features resembling MS pattern II and pattern III (ie, macrophages containing antibody or complement markers, and oligodendrocyte apoptosis with preferential loss of MAG, respectively) can be simultaneously found in a subset of active demyelinating NMO supraspinal lesions."

    "These features strongly resemble the characteristics of the stage-dependent heterogeneity that Barnett and Prineas described in the prephagocytic/active demyelinating lesions and raise the possibility that the index case described by Barnett and Prineas was NMO rather than MS.This is further supported by the aggressive clinical course in their pediatric patient with relapse-related disability, including an episode of myelitis as well as severe brainstem dysfunction, leading to death within 1 year of onset."

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915566/

    ReplyDelete
  10. "Remove EBV and lessions vanish from MRI"
    Are you talking about MS lesions (ATA188), or EBV brain infection lesions? Please provide link.

    Last time i checked, both MS and NMO are officially of unknown etiology . As far as anyone knows, their pathology could be very much the same. So, the argument above is the following statement in disguise:
    "this lesion, whose formation i can not describe (MS), might be the result of some other process, of which i have no clue (NMO)."

    Regarding the aquaporin-4 antibodies argument, one should notice that aquaporin-4 rich brain parts (like cerebellum) are usually unaffected by NMO lesions. Even so, no one knows how NMO lesions really evolve.

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    1. Do EBV brain infection lesions ever last for 20 years ?

      "Panel E demonstrates three periventricular gadolinium-enhancing lesions (arrows) 5 weeks before the commencement of therapy whereas Panel F shows no enhancing lesions 9 weeks after the completion of therapy."

      http://journals.sagepub.com/na101/home/literatum/publisher/sage/journals/content/msja/2014/msja_20_11/1352458514521888/20170110/images/medium/10.1177_1352458514521888-fig1.gif

      "AdE1-LMPpoly is a novel recombinant adenovirus vector encoding multiple CD8+ T-cell epitopes from three EBV latent proteins, namely EBV nuclear antigen-1 (EBNA1), latent membrane protein 1 (LMP1) and LMP2A.7 Adoptive immunotherapy with autologous T cells expanded in vitro with AdE1-LMPpoly increases survival in patients with metastatic nasopharyngeal carcinoma, where the EBV-infected carcinoma cells express EBNA1, LMP1 and LMP2A.7 Because EBV-infected B cells in the brain in MS express the same three EBV proteins,5,8 adoptive immunotherapy with AdE1-LMPpoly might be an effective way to increase the number of CD8+ T cells available to eliminate EBV-infected B cells from the CNS. Here we report the use of adoptive immunotherapy with AdE1-LMPpoly to treat a patient with secondary progressive MS, for which currently there is no effective treatment."

      http://journals.sagepub.com/doi/full/10.1177/1352458514521888

      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/

      Delete
  11. Thanks for being called a myth-buster profG..

    So the first question I have is.....Is this really a 17 hour lesion?

    Come-on look at all the loss of blue in the image you show. There is substantial loss of myelin.

    Has this all happened in 17 hours. I would really doubt this very much...this must be days or more old.

    What has been clearing up the myelin debris.

    What has happened in this time interval.

    Maybe Dr Gay can comment would such extensive myelin loss occur in 17 hours.
    If not then the central thesis of the study falls apart as it based on false evidence.

    In a few days in animals a causative perivasuclar lesion could have come and gone was the causative lession in the next section the whole tissue wasnt sampled I bet. etc etc etc,

    The figures show a oligodendrocytes dying with out too many T cells in sight.

    Do they have to be in sight?, They are there as it says few lymphocytes not no lymphocytes.

    In the world of immunology you ask,

    How do CD4 kill oliogodendrocytes the answer is surely not by direct killing.In EAE we know that CD4 T cells cause the disease but really how does the demyelination occur.

    Oligodendrocytes do not express MHC class II and therefore are not going to be killed by cell-cell contact. So they don't need to there to kill

    T cells are going to be activated by an antigen presenting cell e.g a microglia as they express class II.

    So the only way to kill is with a soluble factor which can diffuse some distance into the tissue or they instruct other cells to kill or they deliver a suicide signal.

    Not sure we EAEers have answered this when EAE is so clearly CD4 T cell mediated.

    Next up we have CD8 and they could recognise oligodendrocytes by class I and do a direct cell-cell killing but enough of the CD8 were not seen.

    Next we have the B cell how could this kill oligodendrocytes, maybe be releasing toxic cytokines or importantly by producing antibody. This is small and soluble so not visible unless you stain for it in the sections. It can be produced a distances along way from the target. Antibody + microglial = cell death.
    y matter lesions and the distribution says to me that there is something soluble at work.

    I think they looked for antibody but didn't find it but cant remember.

    Was there tissue lack of oxygen (hypoxia), which could kill at some distance away.

    Then there is the pre-active lesion of Dr Love and the oligodendrocyte lesion type II and type IV seen in biopsies and so is this not quite the rule but an exception.

    In the preactive lesions of Doctor love we have an oligodendrocyte surrounded by microglia. The oligodendrocyte is expressing a stress proein HSPB5 = CryAB= Alpha B crystallin. What is causing the oligodendrocyte to express the stress protein. Is this an infection?

    A logicical possibility is is EBV doubt it, is it JC?

    The technology exists to do single cell capture, PCR, the contents of these oligodendrocytes need to to sampled and deep sequenced to see if there is an active virus in them, there will be inactive viruses in them because all cells have them. Is this the problem and it is endogenous retrovirus.

    The Prineas paper was years ago and ample time for this to be done...maybe it has and they found nothing. Maybe pathologists need to stop simply looking and start doing.

    These pre-active lesions are common so you don't have to wait for the magic case study.

    ReplyDelete
    Replies
    1. What has been clearing up the myelin debris.

      These observations, and the fact that myelin sheaths
      throughout such areas are detached from viable oligodendrocytes,
      suggest that innate macrophage scavenger
      activity, rather than typical T-cell–mediated macrophage
      activation, underpins macrophage-myelin engagement
      in MS. Consistent with this are reports describing
      active myelin phagocytosis in MS lesions with
      few T cells and absent B cells and plasma cells in patients
      who have received intense immunosuppressive
      treatment.49,50 Thus, myelin phagocytosis in MS appears
      to be an innate immune response directed at degenerate
      myelin, similar to that seen in traumatic and
      ischemic lesions where a rapid influx of monocytes and
      transformation of ramified microglia result in rapid removal
      of degenerate tissue.

      Delete
    2. Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions. Macrophage
      activity is largely an innate scavenging response to the presence of degenerate and dead myelin. Adaptive immune
      activity involving T and B cells is conspicuous chiefly in recently demyelinated tissue, which may show signs of oligodendrocyte
      regeneration. The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed
      against a myelin or oligodendrocyte antigen.
      Ann Neurol 2009;66:739–753

      Delete

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