Research:Primary oligodendrocyte death does not elicit anti-CNS immunity


Locatelli et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nature Neuroscience (2012) doi:10.1038/nn.3062 [Epub ahead of print]

Anti-myelin immunity is commonly thought to drive multiple sclerosis, yet the initial trigger of this autoreactivity remains elusive. One of the proposed factors for initiating this disease is the primary death of oligodendrocytes. To specifically test such oligodendrocyte death as a trigger for anti-CNS immunity, we inducibly killed oligodendrocytes in an in vivo mouse model. Strong microglia-macrophage activation followed oligodendrocyte death, and myelin components in draining lymph nodes made CNS antigens available to lymphocytes (white blood cells) . However, even conditions favoring autoimmunity—bystander activation, removal of regulatory T cells, presence of myelin-reactive T cells and application of demyelinating antibodies—did not result in the development of CNS inflammation after oligodendrocyte death. In addition, this lack of reactivity was not mediated by enhanced myelin-specific tolerance. Thus, in contrast with previously reported impairments of oligodendrocyte physiology, diffuse oligodendrocyte death alone or in conjunction with immune activation does not trigger anti-CNS immunity.
When I first read the comment in the blogger comments that the “Neurodegenerative hypothesis for the causes of MS is obsolete and researchers should be looking at the immune system and not the CNS” I thought that they were taking about the neurodegenerative hypothesis in progressive MS. To think that this is caused by influences outside the CNS and the immune system, is just pants, because I do not think the (lymphocyte) immune system is the problem there.

the neurodegenerative hypothesis is a hypothesis (idea) not about nerve damage (neurodegenerative) but an idea about oligodendrocyte damage, so gliadegenerative. This study is looking into the idea that oligodendrocyte damage is a trigger for immune attack in the first place.

As you know when you look at MS there is evidence of oligodendrocyte damage often in the absence of lymphocytes (a type of white blood cell), which some people think cause the problems with multiple sclerosis. This oligodendrocyte damage is thought by some, to trigger an immune attack of more oligodendrocytes. What causes the oligodendrocyte damage is unproven some may say viral attack others will say an inappropriate immune attack. So what did this study do?

They made a genetically-engineered mouse where the myelin-forming cells called oligodendrocytes make a target for the diptheria toxin which in normal mice would do nothing, but in these genetically engineered mice it causes the destruction of the oligodendrocytes so you have oligodendrocyte death so what happened next? Did the mice develop multiple sclerosis-like disease, even when in an inflammation-prone state? Well the answer is NO….so the conclusion that death of oligodendrocytes is not enough to cause immune attack of further oligodendrocytes. So we have to think about a different way that multiple sclerosis can be triggered. The solution is we should look outside the brain to work how MS starts. Hmmm not so sure.

Now the first thing that some of you will say is that, this is animal work and animals do not get MS and so blah, blah, blah… once you decide to read-on, you have moved away from this counter-productive response.

Then there are the others that will say that this study shows that MS is not an autoimmune disease caused by and causing oligodedendrocyte destruction. Indeed there are many like Prof G that think that this work will further support their view that the cause of MS is the work of some thing like a virus and this autoimmunity stuff is all guff. This is the message that this paper is attempting to get across…….. they may be right, so bring on the Charcot Project. They killed oliogdendrocytes and caused demyelination but this did not lead to lymphocyte activation and did not cause an MS-like disease. They looked but could not find evidence that damage to oligodendrocytes can trigger MS attacks.

However, the problem of getting experiments that essentially do not work as planned could mean that rather than the idea being wrong, the wrong experimental design was used. So the autoimmuners still have a way to keep their beliefs and accomodate this new study.

So what did the study show? Well if you kill oligodendrocytes you get demyelination and animals (and presumably humans) develop neurological sysmptoms as a consequence of demyelination. Indeed in this study the mice actually died and this is perhaps a problem as this down-hill spiral (of about 2-3 weeks) may have been too quick for a proper destructive autoimmune response to develop. This takes time in animals and humans. They did try and reduced the amount of toxin to limit the amount of nerve damage and did this over months and still no MS-like disease. The researchers were looking mainly in the brain for the autoimmune response, when the autoimmune response may accumulate first in the spinal cord of mice as we learned previously (can you remember the gate in the lumbar spinal cord?)

Now next point they show that if you loose myelination, nerves are vulnerable to nerve damage. Indeed in this study the pictures tended to suggest that nerve loss may be dominant effect, as they really did not present very good evidence of long-standing demyelinated nerves, which we think occurs in MS.

They showed that they could not find evidence that the damage created by loss of oligodendrocytes in the brain led to lymphocyte stimulation in the lymph glands. However, the white blood cells they used to try and cause the MS-like disease, do not do their supposed job in some peoples hands. There are a few more experiments that could have been done that would clarify this, but we can say that for any piece of work.

Is this result surprising? Well perhaps not because there have been studies, in other similar genetically-engineered mice that show dysmyelination and demyelination and the development of autoimmunity was not yet reported. The strain of mouse they used has low susceptibility to MS-like disease, so maybe they did not model the genetic predispositions well enough as we know that many different factors come into play when MS is triggered.

However maybe the autoimmune hypothesis of MS is wrong and this is further evidence to support that view. Alternatively it may be that the anti-myelin autoimmune response is wrong and that the target in oligodendrocytes is something else. Time will tell. However if autoimmunity is a problem in MS, it is more likely that it is first stimulated in the lymph glands and then the damaging cells enter the brain. This is because the lymph glands are structurally specialised for this operation, the brain is not.

If indeed you can induce robust demyelination, without losing too many nerves, and killing the mice, These animals could be of real use in working how to promote remyelination. In this paper they report some evidence for remyelination so maybe just maybe.

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  • the criticisims expressed in this comments are indeed interesting. However, I'm the first one saying that mouse models are unlikely to model MS (especially RR MS) since we know so little about it…Our work however is very interesting in two respects. 1-oligodendrocyte death is surpsisingly not immunogenic. even when you push the system strongly towards inflammation. 2-neuronal death is the real bad guy. the focus of future research, in my opinion, should be on this.

  • Yikes hunted down by the author lucky for vv he did not comment of maybe he could have had a verbal kicking from the author or maybe vv would shake Giuseppe's Locatellis hand

    Thanks to Giuseppe Locatelli for the comments, but based on his I guess he won't be working on mouse MS models anymore, as he things they are no good

    I am sure the readers will be happy to know that Giuseppe is now focusing on nerve death.

  • Nerve death is indeed where the focus should be. You can't remyelinate nerves that no longer exist for instance. Hopefully a lot more funding will be targetted towards neuroprotective therapies as there's only so much we can do on a wing and a prayer!!

  • Why do you say he won't be working on mouse MS models anymore? I thought everybody says that mouse models don't really model MS, but everybody still works with mice.
    And can't nerve death be studied in mice?

  • It was like hearted :-), I think you will find that most people who work on mice believe that they are looking at something useful. If you don't think it is useful, why do it?

    Nerve death can indeed be studied in mice just as can relapses.

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