Friday, 21 July 2017

Autoimmunity in MS: Neurofilament light

Puentes F, van der Star BJ, Boomkamp SD, Kipp M, Boon L, Bosca I, Raffel J, Gnanapavan S, van der Valk P, Stephenson J, Barnett SC, Baker D, Amor S. Neurofilament Light as an Immune Target for Pathogenic Antibodies. Immunology. 2017. doi: 10.1111/imm.12797. [Epub ahead of print]

Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunisation with neuronal antigens such as neurofilament light NF-L, a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, while antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF-L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration.

When nerves are damaged they breakdown and release their contents and these products are measured as a marker of disease activity. However, it is clear that neurofilament directed antibodies are generated to clear up these breakdown products. 

We have shown that if you cause the antibodies to be produced in mice that they can cause neurological problems. 

This study shows that these antibodies, however can be potentially damaging and so clearly shows there is autoimmunity occurring in MS. In this study neurofilament specific antibodies were injected into animals and it made EAE worst, once T cells had opened the blood brain barrier to allow the antibody to enter the brain. This was not surprising as this has been shown with a number of antibodies. More surprisingly when injected directly into the brain these antibodies caused signs of disease. It was surprising because neurofilament is inside a nerve and so would not be easily assessable.  The signs occurring were very different to the signs occurring when antibodies targeting basal ganglia from a person with a tic disease was injected into the brain. 

These neurofilment directed antibodies can kill nerves and so could contribute to damage in MS.

CoI. This is work bt TeamG

14 comments:

  1. "clearly shows there is autoimmunity occurring in MS"

    No, it clearly shows there is autoimmunity in EAE. What is more, except for antibody production, there are always compensating mechanisms to limit their destructive force on normal tissue. By simply transferring antibodies, one does not take this action into account.

    If your statement was true, MS would be a one-way, short-termed, culminating disease.

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    "However, it is clear that neurofilament directed antibodies are generated to clear up these breakdown products. "

    Come on, be brave! Say the same for myelin products! After all, myelin is clearly damaged well before scavenging lymphocytes get in through BBB.

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    1. Wrong because we purified the antibody from people with MS.

      Happy to say the same for myelin breakdown products too, just that they don,t occur in MS very often, the antibody response is seldom targeted to myelin.

      Delete
    2. "Wrong because we purified the antibody from people with MS."

      Exactly my point. You transferred the antibody alone, detaching it from the immunological environment where it was created. In MS, this antibody does not appear alone. Steps are taken to restrict its action so that autoimmunity won't occur.

      "the antibody response is seldom targeted to myelin."
      Still, myelin is not healthy when lymphocytes arrive. It gets damaged even before microglia get hot. Actually, the latter are the first immune response to damaged myelin. When the damage exceeds their cleaning capacity, they call T & B cells for backup.

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    3. These antibodies are clearly neurotoxic, so it appears your propsed "steps" are a figment of your admitedly fertile imagination.

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    4. Of course they are neurotoxic. They are supposed to break down damaged axons, so that reparation processes take place. But it is wrong to take out a piece of a complex immune process, the full picture of which you don't have yet, and accuse it of this and that.

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    5. By that reasoning, no-one would do anything.

      Delete
  2. Sorry but i dont understand (and dont have acess to the paper):

    1º neurofilament light NF-L "Neurofilaments (NF) are the 10 nanometer or intermediate filaments found in neurons. They are a major component of the neuronal cytoskeleton, and are believed to function primarily to provide structural support for the axon and to regulate axon diameter"
    2º"These three proteins are often referred to as the "neurofilament triplet", and numerous specific antibodies to these proteins have been developed and made commercially available. Such antibodies are widely used to identify neurons and their processes in histological sections and in tissue culture"(wikipedia)

    3ºHas i understand nuerons fall apart and the debris(neurofilament light NF-L)can be fond in csf...Right'

    4º In wikipedia they say "Such antibodies are widely used to identify neurons and their processes in histological sections and in tissue culture"
    But in your paper you inject peripheraly antibodies in the mouse model? what are those antibodies?
    5ºAlso if antibodies are produces my b cells,plama cells and eae is a tcell disease where are those antibodies been produce?

    I am confused ...

    Thanks
    Luis

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  3. Am I right in saying that this does nothing to allay the possibility that MS is - in the first instance - a disease of neurodegeneration?

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  4. Also i thought that "the garbage disposal of the immune system" were the macrophages not the antibodies

    Luis

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  5. We inject anti neurofilament antibodies.

    Antibodies can be induced by artifically sensitizing to neurofilament

    However they occur naturally in MS because I suspect people are being sensitized by the neurofilament breakdown products that are in the blood

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  6. Is there any data on measuring nfl-l ab/ag levels in the peripheral blood as a marker for disease progression?

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  7. I started on avonex after 7 months from my diagnosis i had only on lesion
    i was fine after the steroids

    Then all the hell braked loos with avonex
    I used have a relapse every month with avonex with major depressive disorder and hallucinations

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  8. MD, would these autoantibodies to neurofilaments be responding to a certain antigen in the CNS or to something that would be used in a form of "molecular mimicry"?

    Also, as far as I read, it seems that the concentration of these autoantibodies to NF-L is higher in the blood than in serum and cerebrospinal fluid, right ?
    So could the plasma cells be "catching" them out of the CNS?

    Another question I have is where, at what point in the chain of events of MS do these autoantibodies to NF-L fit together, soon after the entry of the T cells by the BBB breach, or together, or preceding them?

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    Replies
    1. I dont know by I suspect they occur as a consequence of prior damage

      Delete

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