Yet another idea of how MS starts


van Noort
JM et al. Mechanisms in the Development of Multiple Sclerosis
Lesions: Reconciling Autoimmune and Neurodegenerative Factors.
CNS Neurol Disord Drug Targets. 2012 [Epub ahead of print]

Both immune-mediated and neurodegenerative processes play a role in the
pathogenesis of multiple sclerosis (MS). There is still considerable
debate, however, on how to link these two seemingly unrelated elements
in disease. It has also remained unclear how the immune system can be
involved without harboring any obvious myelin-directed abnormality in MS
patients. Here, we propose that the unique properties of a small heat
shock protein, HSPB5 (alpha B crystallin), can help reconcile the role of the immune system
with the neurodegenerative element in MS, and explain the absence of any
peripheral immune abnormality in people with MS. By being selectively induced
as a protective stress protein in oligodendrocytes, and subsequently
triggering activation of nearby microglia, HSPB5 accumulation translates
neurodegenerative signals into a local innate immune response. The
immune-regulatory profile of HSPB5-activated microglia, as well as
animal model data, indicate that the HSPB5-induced innate response is
neuroprotective. However, the presence of pro-inflammatory
HSPB5-reactive memory T cells in the human immune repertoire, a unique
feature among mammals, can subvert this response. Recruited by the
innate response, such T cells respond to the accumulation of HSPB5 by an
adaptive immune response, dominated by IFN-gamma production, that
ultimately overwhelms the originally protective microglial response,
and culminates in tissue damage. Thus, HSPB5 accumulation caused by
neurodegeneration can provoke a destructive local adaptive response of
an otherwise normal immune system. This scenario is fully consistent
with known causative factors and the pathology of MS, and with the
effects of various therapies. It also helps explain why MS develops only
in humans.

There is very little evidence to support the role of myelin basic protein autoimmunity in the development of MS. This myth has been peddled by “fundementalist immunologists”, who could only make MBP. This is because it was water soluble and easy to make not because it was a logical target for autoimmunity. But when you take an unbiased approach and ask what T cells react with in MS brains the answer appears to be HSPB5. This is the number one protein that is upregulated in MS lesions.

People talk about “outside-in” and “inside out” mechanisms of autoimmunity, but if it is autoimmunity that comes into play it is in my opinion likely to be “outside-in” because the CNS does not support the generation of an aggressive immune response. This is because it does not contain the cell types that would trigger this. The naive immune response does not enter the CNS because the vascular does not produce the right signals to pull immune cell into the brain. This occurs in the lymph glands. T cells are educated to recognise their potential targets in the thymus. The thymus of essentially all animals contain HSPB5 and therefore T cells are deleted from the immune repertoire by a process called negative selection. Therefore in virtually all animals HSPB5-reactive cells do not exist. 

However, this does not occur in humans and so HSPB5-reactive cells can be generated and are not deleted. They can enter the blood and will home to the lymph glands. When humans are infected by EBV the immune response is stimulated and his causes the production of HSPB5 by the B cells. These can act as antigen presenting cells and stimulate HSPB5 reactive T cells such that they mature. These cell up-regulate markers used by white blood
cells to get into the brain. If they get in the brain and do not find
something that stimulates them, they die and are cleared away. But if they see HSPB5 damage can occur.

Healthly and MSers have cells that react with HSPB5 and 1 in 30,000 T cells react with this target. In the CNS of healthy individuals there is no expression of this protein, but in MS it is the number one upregulated protein.

We produce thousands of new immune cells every day so there is not reason that we need to let them escape. However if HSPB5 is stimulated to be expressed in the CNS it can be a targeted for destruction by the HSPBB5 reactive cells.

When the trigger of oligodendrocyte damage occurs in MS whether this is due hypoxia, viral or antibody or cytokine attack oligodendrocytes produce HSPB5, because this is a cell protection protein. It is aimed at helping them cope with disease such that they can stop nerve damage. When stressed to produce HSPB5 the oligodendrocytes stimulate the activation of microglia, if they produce certain growth factors it may alow the oligodendrocyte to deal with the damaging stimulus but in the presence of pro-inflammatory cytokines they can stimulate damage particularly in the presence of HSPB5 reactive T and B cells and damge to the oligodendrocyte can ensue. So the trigger for MS occurs in the CNS but independent events outside the CNS contribute to this..and I don’t mean neck veins

There are many more possible explanationsof how disease develops but this can accomodate many of the the observations that occcur in MS.

CoI. Written by members of Team G

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Leave a Reply to Iain O Cancel reply

  • So if you were looking for a potential target for a therapeutic agent would it be the HSPB5 reactive T cells? If HSPB5 is neuroprotective in the first instance you wouldn't want to stop its work, or the B cells that produce it, or are some of the emerging DMT's that affect B cells affecting their production of HSPB5?

  • It maybe neuroprotective if present in nerve and cytoproctive in oligodendroytr oligodendrocytes.

    with regard B cells you do not want it expressed as it drives T cell response

    With regard targeting the T cells, this is ongoing in MS as we speak
    but needs to use a depeltion agent in the trial design which it does not have.

  • Two questions:

    1. Could monitoring of HSPB5 be a good bio marker to see drug efficiency in MS DMTs?

    2. What drugs might downregulate HSPB5?

    For instance, I wonder if there is any evidence that Nicorandil could help with MS?

    It has had some evidence in mice of cardioprotection – and it "appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in HSPB5 R120G TG mice". (Interesting , given the link to possible mitochondrial protection given your previous post about mito impairment and its suggested role in progression).

    Mouse Doc – fancy popping a couple of angina pills into one of your cheese nibbling friends? You could mix it in with their cheddar.

  • Iain O

    Not sure downregulating HSPB5 would be a good idea as these proteins are protective in times of cell stress as in an immune attack. Downregulating it might kill off all those cells that would survive. We need to get rid of the autoreactive T cells that react with this antigen.

  • Good answer.

    And there was me thinking I had found a cure and was going to win a big fat prize or something.

    Images of grandeur fade into a haze of reality….

  • Oligodendrocytes release HSPB5 because something damaged them in the first place. So they will die irrespective of any reaction to the HSPB5, and take the myelin down with them. So what's the point in suppressing HSPB5 T-cells?

  • So they will die….

    Not necessarily the HSPB5 appears to be a protective mechanism.

    There are more preactive lessions than appear to develop into real leasions suggesting that some of these events lead to cessation of the attack and stops the death of oligos.

    Look at the figure and this point was already made.


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