“I am reposting this for those of you have not had time to read all the posts on this blog.”
“This study really challenges our understanding of MS; it challenges the dogma!”
The investigators present the pathological findings in 12 patients with RRMS who tragically died during or shortly after the onset of a relapse. Microscopic 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 drive autoimmunity and enter the brain and spinal cord from the peripheral blood. Natalizumab is believed to work by blocking this migration of lymphocytes. 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.
“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 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? This story still has a long way to run. I will keep you posted.”
* 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
29 thoughts on “Article of interest (2): Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion”
I have been following this blog for a while now and it amazes me just how much more knowledgeable I feel about MS and the powers that are shaping the progression of my disease. I often refer to the arguments on this site when I talk about MS with my dad, saying “well, Prof G said this” or “some commentator on Prof G’s blog argues that”. This means that this blog has become somewhat of a multiple sclerosis oracle for me, but I suspect therein lays a problem.I am not a scientist and I suppose many of us who read this blog are not either. We are people who have MS and want to know as much as possible about this disease that is not currently curable and remains largely untreatable. There may be some other expert neurologist out there who can present an equally potent argument on why MS is not caused by a virus and is in their view an auto-immune condition, but because that neurologist is not actively online and able to simplify their claims, it’s hard to get their side of the argument.Nonetheless, I sort of buy Prof G’s thoughts on MS being a viral condition because I distinctly remember getting a cold before my MS symptoms set in. I got over the cold but there was something strange that lingered, causing extreme fatigue and subsequent walking problems that ultimately got worse. I think that the cold I suffered may have triggered my MS, though this is like an earlier commentator in another post said, is “supposition”. I would very much like to know if any other people with MS experienced something similar to me when their MS came about.
We are aware the the science is complex, and we still have a lot to learn, but that shouldn't put us off trying to explain things. Which is what we are trying to do. The viral and autoimmune hypotheses are not mutually exclusive. Viral infections can trigger and drive autoimmune reactions; there are plenty of well-defined diseases were this has already been established. Why this is important to establish is that if it is a virus, say EBV, then treating MS with a specific anti-viral drug may be more effective than targeting the immune system downstream of the trigger. Some of the drugs we use against the immune system are like sledgehammers and leave the people at high risk of complications, for example infections and secondary malignancies.
Prof G,The work by Prineas & co sort of illustrates the problem with the current model of trying to crack this disease. What was really interesting was that this work was published in 2004, but 7 years later there is no agreement on what it shows etc. There has been some big funding directed at pathology e.g. The Lesion Project and the UK Tissue Bank. However, it looks as if we are still no nearer to identifying the chain of events which underpins this disease!
Prof G, what about the theory that neurodegeneration (axonal damage) is the first thing that goes on in MS and inflammation/immune responses are secondary?
Re "neurodegeneration (axonal damage) is the first thing that goes on in MS and inflammation/immune responses are secondary": This is still very much on the cards. The long-term follow-up of PwMS treated with Natalizumab and Alemtuzumab will answer this. If they stay well without the development of SPMS after 15-20 years we can confidently say that inflammation drives neurodegeneration. The corollary of course is if PwMS come back with SPMS despite adequate control of inflammation early on….
So how would this work? Are you suggesting that the nerves are degenerating inside their myelin protection anyway irrespective of inflammatory attacks on the myelin? Would this be because a virus continues to attack them inside the myelin when viral drugs might help, or the initial attack is over and the nerves just continue to degenerate. What would be the point of remyelinating therapies,apart from slowing down progression?
BeverlyThe jury is out on whether it is a primary death of the nerve. What is clear is that after attacks nerves continue to die for a number of reasons after an inflammatory episode. If the nerves have died then remyelinating therapy is pointless as there are no nerves to remyelinate.The trick is to stop the nerves from dying so that remyelination can occur.We are working hard on this.
Parts of the study:"an abrupt loss of oligodendrocytes throughout a circumscribed and relatively small volume of tissue.""Within hours, oligodendrocytes throughout the affected tissue appear apoptotic"Within hours something kills oligodendrocytes within a well defined region and then stops at the same time to all directions. Can i virus do that? If yes, why does the attack begin? Why against oligo? Why does it stop? How can all virus particles stop at the same time? "Inflammation is associated with postapoptotic necrosis, which occurswhen normal clearance mechanisms of apoptotic cells are overwhelmed,and it is possible that this mechanism contributes to the inflammatory response in MS."The inflammation comes as a helping hand to clear the mess. It is therefore useful and only a sign of the damage, not the damaging process itself.It seems that the problem with solving MS is not due to its hard nature but on the fact that the right questions have not been asked yet.
VV, I'm not a scientist but even I can see that that your conclusion that because inflammation is useful and only a sign of damage,it is not the damaging process itself, is flawed. Why can't it be the damaging process itself?
VVYou also seem to buy into another contentious theory, namely protective autoimmunity. If this exists it is very different to the florid inflammation seen with MS lesions, which is definitely damaging.
Beverly, it doesn't need to be in order to explain the mess inside a lesion: The oligodendrocytes are dead, the myelin is starting to disintegrate, and the immune system is not even there. What happens when it gets there? It simply begins to digest the broken down myelin and gives you the impression of destroying it. Please, take some time and read the full article and the rest Prof Prineas has published.MD2, the question is why no one bothers to explain why oligos die in the first place, but so many blame an apparently justified inflammation?
VV, thank you for suggesting I read the article. Perhaps you would also like to look at the research; damaging microglia that was published on this blog in Dec 2011?
"It simply begins to digest the broken down myelin and gives you the impression of destroying it."There's a lot more to it than that as explained by the fact that if you stop lymphocytes getting into the CNS, no lesions.
Beverly, i read it. The axons could very well be already damaged, just as the myelin surrounding them. There is no proof that microglia act against healthy axons.
MD2, what about stopping oligos from dying? That way there will be no need to prevent lymphocytes from getting into the CNS.
How do you (vv) propose that we stop the oligodendrocytes from dying?
By preventing injurious venous blood flow reversals from inflicting the brain parenchyma. Try creating them in a mouse model and see what happens. You may ligate their jugulars and put them into demanding activity or you may rapidly push blood from their jugulars back to the brain.
Vv, so you are implying that Prineas' work supports some kind of vascular pathology that results in oligodendrite destruction before the involvement of lymphocytes, hm?Anyway, was the fact that this unfortunate girl had an upper respiratory tract infection 2 weeks before her fatal relapse in any way relevant to her death? She was given high dose steroids when she arrived at the hospital but later went into cardiac arrest and died. Is there any intervention available now that would have saved her life (this case occured in 2004)?
"By preventing venous flow"hmmmm http://multiple-sclerosis-research.blogspot.com/2012/01/what-is-your-story.htmlTherefore John Prineus did address your view with his rather different view. Please read (http://multiple-sclerosis-research.blogspot.com/2011/12/guest-post-john-prineas.html) so there was no point in asking about autoimmunity!"Try creating them in a mouse model and see what happens". Not sure why I would want to do this but no doubt there is someone out there……but there are plenty of vessel occulsion models out there.
Re "Vv, so you are implying that Prineas' work supports some kind of vascular pathology that results in oligodendrite destruction before the involvement of lymphocytes, hm?"No, Prof Prineas' work sets aside the autoimmune and the viral hypothesis. The vascular pathology comes from the topography of the cerebral MS lesions and especially Dawson's fingers. The thing is that it does not seem to contradict Prof Prineas' conclusions.Re "Therefore John Prineus did address your view with his rather different view"He mentions "the sort of vascular pathology that has been proposed." I wonder which did he had in mind, the static Zamboni model of iron accumulation or the dynamic Schelling model of swift blood reversals. I 'm always talking about the latter. I don't buy the iron accumulation as cause of MS.
Re "Anyway, was the fact that this unfortunate girl had an upper respiratory tract infection 2 weeks before her fatal relapse in any way relevant to her death?"Only doctors can tell. However, the infection points to some kind of immunomodulation/suppression she was probably under.Re "She was given high dose steroids when she arrived at the hospital but later went into cardiac arrest and died"Steroids are not at all innocent. This blog has made that clear quite often.Re "Is there any intervention available now that would have saved her life (this case occured in 2004)?"Of course there is. But it's not fine-tuned for all cases yet. But progress is exponential taking into account that 3 years before no one practiced it.
"Is there any intervention available…..of course there is……. progress is exponentialWhere is the hard evidence?
"Prof Prineas' work sets aside the autoimmune and the viral hypothesis"No it does not……you can still accomodate autoimmune and viral views into this world view.I does asks questions the lymphocyte "outside-in" view and suggests an intrinsic CNS problem.
Where is the hard evidence?This is a retorical question, so I do not need a reference list.
"The thing is that it does not seem to contradict Prof Prineas' conclusions".Prineas conclusions in his own words that he did not see evidence for vascular pathology. This is a contradiction?
The Zamboni verses the Schelling viewin simple English that needs a post……..not sure we will get too many volunteers though.Maybe anyone interested, can do their own research to be found elsewhere.
If there really is HARD evidence THEN SHARE IT. WE CAN REJOICE AND FIND NEW DAYJOBS. .SURELY IT WOULD BE SPLASHED ON EVERY FORM OF MEDIA.
"Try creating them in a mouse model and see what happens"You have often said "Mice do not get MS"…Therefore why would you suggest this experiment?. On the basis of your views surely it would be possible to affect vascular flow and Mice would get MS? More important to build MS epidemeology into your world view of MS pathogenesis
Sorry, my questions regarding the Prineas article were directed at the members of Team G. Re:VV–I just wanted to point out the contradiction between his comments on this post and the previous Prineas post.