Monday, 5 December 2011

Education. Espresso Pathology. Lesion formation

Espresso Pathology: Lesion formation

We recently looked at different cell types that make up the brain tissue, now we see how they are involved in, and are attacked during multiple sclerosis.

A pathologist (someone who studies disease) such as myself or Doctor PowL will look at brains from MS'ers. You can often see evidence of MS with the naked eye by the development of MS plaques (MS lesions), which are areas of scar tissue (circled in yellow).

These are easy to see in the white matter (bit of brain tissue containing the nerve tubes/axons). However, they also occur in the grey matter (bit containing the nerve cell heads) on the outside of the white matter in the brain but on the inside of the white matter in the spinal cord.



The grey matter on the outside layer looks grey and the white matter is inside this

However, to see a lot more pathologists must look down a microscope and stain the different cell types with specific dyes so that we can see them. If we make a slice through the brain of spinal cord and look in the white mattter, which contains the nerve axons (in red). This is surrounded by myelin (green). This tissue would contain oligodendrocytes, astrocytes and microglia but we haven't added them as it will make the picture look a bit messy. In the magnetic resonance imaging (MRI) scanner you can't see anything abnormal.

The lesions of MS are typically concentrated around small veins (venules) and a single vessel has been highlighted (white edges) above. Although there may be other explanations we believe the first event of MS is due to a problem with the oligodendrocyte (could it be that it is being infected with a virus or are these cells stressed? Although some of you may think this is a problem caused by the vasculature abnormality, evidence of this is relatively lacking). This damage is spotted by the microglia, which become activated. We call this the pre-active lesion. There we can see clusters of microglia (brown cluster below) and often oligodendrocyte damage (loss of myelin).
There lesions may resolve (get better), but when the microglia become activated they can secrete molecules that will trigger the lining of the blood vessles to produce molecules (Flags) that can be seen by passing white blood cells that tell them to enter the blood vessel. This occurs in venules (small veins that carry blood from the tissues to the heart) because this is where the blood pressure from blood flow is lowest so it is easy for the white blood cells to slow down and stick to the blood vessel wall.

The white cells push their way through the blood vessel cells (endothelial cells) and form a perivascular cell cuff (picture on right shows white blood cells around a blood vessel) around the blood vessel and this can be seen as Dawsons fingers when they occur around the ventricles (fluid filled space in the brain). At this stage they haven't entered the brain tissue but as they are kept within the glia limitans which is a membrane formed by the foot processes of astrocytes that are present below the blood vessel wall. In MRI (there are two obvious lesions at one and nine o'clock and probably another a 4 o'clock relative to the position of the brain in the example below) this can be seen as a gadolium-enhancing lesion and is known as an active lesion. The cells in there lesions are often lymphocytes (white blood cells known as T and B cells) and macrophages. Granulocytes are less common. This suggests that there in an immune problem in MS and is consistent with the finding that the genes that have been linked to susceptibility to MS are associated with the function of the immune system.
The cells then burrow through the glia limitans and enter the parenchyma of the brain (brain tissue) and the macrophages are a common feature and they eat the myelin debris as they expand outwards from the original vessel. This will cause further nearby blood vessels to leak such that the MRI can see a ringed structure (lesion at 1 o'cloc in the picture below) behind a quiescent centre of the lesions. This is called chronic active lesion. There is a dense region of macrophage activity at the lesion rim and the macrophages are full of lipid droplets because they are eating the fatty-myelin sheath (red stuff is lipid in the right-hand bottom picture below).
MS lessions expand for about two weeks to a month and then the immune response is down regulated by some poorly understoood mechanisms and the white blood cells dissappear and probably die in the brain. The appears to be two paths followed after this, either the oligodendrocytes enter the lesion and start to make new myelin known as remyelination. If remyelination does not occur then nerves may be vulnerable to damage and loss. You can see the myelin sheath (black bit surrounding the nerve in the top left picture below). Demyelination in top right picture (note the black ring in missing). Remyelination (bottom left) is seen by the return of thin-myelin sheaths. Bottom right is a fluid filled space where nerves used to be indicating nerve loss.

Once the immune response is silenced, if the damage is not repaired then astrocytes (yellow cell) enter the lesion and form a scar. This is then difficult to repair via remyelination. This leaves a demyelinated lesion that is called a chronic inactive lesion. This may represent a MRI black hole (one o'clock in MRI image below).
The aim of MS researchers must be to repair the myelin, we need to instigate Prevent MS to stop the the disease from starting. Once it has started we need to stop the white blood cells from getting into the brain to cause damage. We are getting increasingly better at this.
We need to stop nerve damage from occuring once the immune system gets in the brain and we have started to do this to treat MS, then we need to repair the nerve damage. Unfortunately we are at early stages in the investigation of this form of treatment aim.

Next time we will look at lesion variation, which suggests that there could be different triggers, or is it similarity?

33 comments:

  1. Wonderfully informative. Surely we need the white blood cells to be able to enter the brain to deal with random infections? Isn't it better if we can re programme them not to attack us? If it's the macrophages that are the problem and they come from monocytes, can't we just stop them getting into the CNS?

    ReplyDelete
  2. From the description above, it seems like white blood cell have done nothing wrong. They were called by microglia to clean up destroyed myelin following oligodendocyte apoptosis. This is consistent with the very low population of T and B cells compared to macrophages seen inside lesions.

    Re "MS lesions expand for about two weeks to a month and then the immune response is down regulated but poorly understoood mechanisms"

    You mean you don't know why the immune system stops on its own its supposed "attack"? But you are pretty sure that it started one? What kind of science is this?

    Why don't you examine the obvious: the lesion stopped evolving because all myelin debris were cleaned successfully and no harmful viruses were encountered inside the brain.

    ReplyDelete
  3. Re "Although some of you may thing this is a problem caused by the vasculature, evidence of this is relatively lacking"

    Is it?
    1. Why are the lesion related veins often engorged and deformed?
    2. Why do all lesion related veins drain into periventricular veins and eventually into the straight sinus?
    3. Why do pereventricular lesions tend to expand whereas more distant lesions usually come and go?
    4. Why isn't the lesion topology RANDOM?

    Do you consider the above as lack of evidence?

    ReplyDelete
  4. Thanks for clear explanation.

    ReplyDelete
  5. "[W]hen the microglia become activated they can secrete molecules that will trigger the lining of the blood vessles to produce molecules (Flags) that can be seen by passing white blood cells that tell them to enter the blood vessel."

    Are the molecules secreted by the microglia that signal to the endothelial cells, cytokines? And are the "Flags" produced by endothelial cells, selectin molecules that attract phagocytes, correct?

    Are the "poorly understoood mechanisms" those related to alternative splicing of RNA and the role it plays in regulating immune responses?

    ReplyDelete
  6. Dear Anon 9:36
    Correct we need white blood cells to enter brains to deal with chance infections. This is what appears to go wrong sometimes with tysabri and as a result JC virus, which is normally kept at bay can cause PML. So better that they are reprogrammed not to attack the brain, if that is what they do. Many think this is what happens a few of you don't.

    Yes it would be good to stop monocytes getting in to the brain if they are causing damage. This is what tysabri may do..we have forever thought about T cells but the action of the drugs could be at the level of the monocyte.

    However we have to be careful as monocytes/macrophages are vital for geting rid of infections,...insects don't have T cell-like cells but do have macrophage-like cells so getting rid of them globally would not be good news.

    However I think macrophage directed drugs is going to be a hot topic for the future. Remember some recent posts there can be go and bad effects of macrophage like cells.

    ReplyDelete
    Replies
    1. But what if the monocyte is infected with a virus when it comes to the rescue much like what happens with HIV? Could it be that the inflammation starts somewhere else in the body and all of the rescuers/cleaning of debris/infection are infected before they arrive?

      Delete
  7. Dear Maria
    Yes you are right,
    cytokines and a special type of cytokine called a chemokine (which a group of proteins that attracts cells subtypes.

    Yes selectins (carbohydrate molecules) and integrins like VCAM-1 to which CD49d binds. This the molecule blocked by tysabri

    Poorly understood mechanisms could those that you say, it could be regulatory molecules such as cytokines, it could be that the target is destroyed because inflammation is about destroy and repair.

    ReplyDelete
  8. Is is eay to present all details as facts...are all MS veins engorged? Do all MS lesion veins drain into the periventricular sinus? etc....answer at present is undoubtedly No...

    Does immunotherapy do anything to lesions?........yes

    You have theories that you adapt and change as evidence develops and is disproved or accepted. Some you believe some...you don't.

    ReplyDelete
  9. If lesion was topography was uniform then the symptoms of disease would be the same?

    ReplyDelete
  10. [1]. Putnam, Tracy J.:
    "Lesions of ""encephalomyelitis"" and multiple sclerosis. Venous thrombosis as the primary alteration. "
    J Amer Med Ass, 108:1477, 1937

    [2] Fog, Torben:
    On the vessel-plaque relationships in the brain in multiple sclerosis.
    Acta Neurol Scand, 40,Suppl.10:9, 1964.

    [3] Fog, Torben:
    The topography of plaques in multiple sclerosis, with special reference to cerebral plaques.
    Acta Neurol Scand, 41,Suppl. 15:1, 1965.

    These researches came out of autopsies. Their conclusions are valid till present day.
    They describe the relationship between lesions and veins.
    You may freely continue to ignore them.

    ReplyDelete
  11. "You may freely continue to ignore them...."

    Did you know that if it wasn't published after the birth of the internet and is easy to get from online library, then to many people it doesn't exist.

    Do you know of any card-carrying (non-italian), WORKING MS-specialist Pathologist who subscribes to this view, who has published on this aspect this centurary?

    Online Acta Neurol 41 Supplement 15 starts on page 7.
    (http://onlinelibrary.wiley.com/doi/10.1111/ane.1965.41.issue-S15/issuetoc. Was page 1 an abstract from a meeting and not a real paper? It is easy to find examples to support many theories.......

    http://theflatearthsociety.org/cms/

    ReplyDelete
  12. I like the 'Repair The Nerve Damage' part best.

    ReplyDelete
  13. P.S. What kind of science is this?

    A humble approach.

    From your take of the lesion as presented by Dr. Love, I am sure Prof G will be happy that you have apparently accepted his viral view.

    ReplyDelete
  14. [4]Adams, C. W. M., Abdulla, Y. H., Torres, E. M., and Poston, R. N.:
    Periventricular lesions in multiple sclerosis: Their perivenous origin and relationship to granular ependymitis.
    Neuropathol Appl Neurobiol, 13:141, 1987

    Climbing up the decades.

    Well, no neurologist/pathologist could halt MS back then, no one can today. Despite the flamboyant modern details, the autoimmune model dates back to 1935, whereas the virus hypothesis even further, 1892 by Pierre Marie. Still, "more research is required"

    I wonder how we bear with our cars riding on 6000 year old inventions.

    ReplyDelete
  15. Laquinomod worked on the monocytes and yet the results were quite disappointing. I note that laquinomod is now promoting its neuroprotective ability. Surely this will be the way research will go now that there are a lot of immunomodulatory drugs either out there or almost ready for market. Neuroprotective and re-myelination drugs that may prevent or deal with progression post immunomodulation would seem to be the future.

    ReplyDelete
  16. "Neuroprotective and re-myelination drugs that may prevent or deal with progression post immunomodulation would seem to be the future."

    That's exactly what we're working on in the lab.

    ReplyDelete
  17. VV
    "You mean you don't know why the immune system stops on its own its supposed "attack"? But you are pretty sure that it started one? What kind of science is this?"

    Firstly your tone is insulting.
    Well, the brain has mechanism such as Fas/Fas ligand that can downregulate inflammation in the CNS, thing is it takes a while to achieve this. This is why in a resolved lesion there are few if any infiltrating inflammatory cells. Stopping inflammatory cell infiltration into the CNS stops lesions so a rational person might surmise they have something to do with lesion development.

    "Why don't you examine the obvious: the lesion stopped evolving because all myelin debris were cleaned successfully and no harmful viruses were encountered inside the brain."

    And where did the myelin debris come from if not as a result of inflammatory insult?

    ReplyDelete
  18. I won't get tired to repeat this:

    "Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes"

    which in plain english means that:
    1. Even new lesions have few T and B cells.
    2. the myelin debris are not the result of inflammatory insult.

    Re "Stopping inflammatory cell infiltration into the CNS stops lesions so a rational person might surmise they have something to do with lesion development. "

    Stopping inflammatory cell infiltration into the CNS stops the collection of myelin debris. The fact that you see the lesion shrink does not mean that the damage is reduced. You simply unplug the "led light" that warns you of the destruction that has taken place.

    ReplyDelete
  19. VV
    "Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes"
    In plain English this means that this paper is swimming against the tide.
    Which paper is this from? There are thousands of papers reporting T and B cells in mS lesions.
    Explain how stopping leucocyte infiltration into the brain prevents relapses and new lesions.
    I suspect anything I or others may say will not stop you banging on but I'm not going to waste any more time on you.

    ReplyDelete
  20. Down with Vasilis Vasilopoulos!Wednesday, December 07, 2011 7:44:00 pm

    Seriously Vasilis Vasilopoulos, you are ruining this blog for everyone.

    You're wasting valuable time with your nonsensical suggestions and criticisms. This is not the forum for you to pathetically undermine scientists that seem to be working diligently in furthering our understanding of MS and generating methods to try and correct the damage caused by the disease.

    If you're such a bleeding expert on MS then why haven't you cured it by now? What the heck is your contribution anyhow? How have you played a role in bettering our understanding MS other than being a total pain in the arse?

    Your feeble CCSVI crusade is wearing very thin my friend and I for one am sick of it. You ought to be booted off this blog somehow. I wish there was an online poll to see how many people who come on this blog are fed up with you.

    ReplyDelete
  21. The more VV and his ilk talk, the less I become convinced about Zamboni's pet theory. But what convinces me even more is that there are cardiovascular experts like Dr. Barry Rubin and Dr. Colin Rose who think CCSVI is rubbish (and have said so publicly), but somehow this fact is conveniently ignored. Maybe VV should ask them why they're not believers instead of coming here and attacking MS researchers.

    Dr. Barry Rubin has treated several MSers for angioplasty complications. Here's a presentation he did on CCSVI: www.uhn.ca/Focus_of_Care/Munk_Cardiac/whats_new/PMCC_Conference/public-lectureMS/video/index.asp#presentation

    Here's Dr. Colin Rose's blog: http://medicalmyths.wordpress.com/

    And yeah, I second Down w/VV's post.

    ReplyDelete
  22. Re "Which paper is this from?"
    http://www.ncbi.nlm.nih.gov/pubmed/20035511

    Re "In plain English this means that this paper is swimming against the tide."

    "The fact that an opinion has been widely held is no evidence whatever that it is not utterly absurd" B.Russell

    Down, you are being ungrateful. I have given you lots of researches to study. Works carefully buried by the volume, not the validity of the opposing opinion. In any case, if anyone is willing to exchange her/his politeness with my MS, then i would happily take the deal.

    ReplyDelete
  23. Vasilis Vasilopoulos, please give it a rest.

    MS brings out the worst in the best of people but your ongoing bitter campaign is annoying me too, and I'm relatively new to this blog.

    Your CCSVI crusade is crowding out more important voices and I think that it will be best if you refrain from posting academic musings most of us, including those running this blog, aren't interested in.

    You need to back off son.

    ReplyDelete
  24. VV, you talk about one of us exchanging politeness with your MS - You do know that most readers here have their own MS? Or they are like me and have a family member with MS? If it was possible I would take that without anything in exchange .

    I wonder how your Prof Prineas wouls react to the manner in which you are using his work

    ReplyDelete
  25. This pathology in the post is the dominant pathology seen in the white matter of the MSers at Post-mortem

    However there are other pathologies found in MSers.

    In the future Dr. Love or I will post on lesion heterogeneitity and similarlity as some lesions have few immune cells (like some Prineus studies) and others have lots of immune cells.

    Then we need to think about Grey Matter lesions that are on the outside bit of the brain (the cortex) which look different because we don't have as much myelin to hoover up (or damage).

    Looking at these, the origin could be products in the meninges which is abit of a way from the ventricles!),

    Looking at the eye which is a very long way from the ventricles and doesn't have myelin is another area that needs explanations. Again theories will need to accomodate.

    But one thing to keep in mind is that it is important to get replication of results

    Look at Prof Gs post today on Grey Matter lesions....these contained immune cells, these people had white matter lesions also (so which comes first....also does this matter?).

    To me they may say virus rather than autoimmune to others it is different. But this needs explanation which is for another day.

    ReplyDelete
  26. "I wonder how your Prof Prineas wouls react to the manner in which you are using his work"

    I'll ask him for a comment

    ReplyDelete
  27. No response from Prof Prineas yet, but I guess he is retired in Australia

    ReplyDelete
  28. "I wonder how your Prof Prineas wouls react to the manner in which you are using his work"

    THE RESPONSE FROM PROF PRINEAS IS IN.....SO WE CAN HAVE NEW FEATURE TOMORROW THE EXPERT COMMENT.

    ReplyDelete
  29. I would think that the first event would be more caused by a problem with the astrocytes since they help form the blood brain barrier. You say that in MS, they divide and become activated (gliosis) and form the scar (sclerosis) which gives MS its name.

    Isn't it stuff getting into the blood brain barrier that allows the myelin sheath to be attacked in the first place, resulting in the scar?

    ReplyDelete
    Replies
    1. please read all the guff on the blog particularly in the education sections it is not so black and white and the lesions you refer to have little to do with blood brain barrier problems

      Delete
  30. I suppose we could say the same thing about the microglia or monocytes, but I would still think the oligodendrocytes are the last step in the process since they are already across the blood brain barrier to begin with?

    ReplyDelete
    Replies
    1. it dependes where you think the problem starts and ends

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.