Monday, 27 May 2013

MS lesions formation

"This highly technical paper explains that the migration of white blood cells into the brain and spinal cord of MSers is controlled by a protein that activates the production of enzymes that white cells use to tunnel their way into the brain and spinal cord tissues. By blocking this regulator, with a drug, you could potentially block migration of white cells into the brain and spinal cord. Is this important? Yes, we already know that blocking white cell entry into the brain and spinal cord is a very effective treatment for MS; this is how natalizumab or Tysabri works. This study describes another way of doing this. I assume Big Pharma are on the case already. How exactly you would do this is beyond the scope of this article, but is very complicated. Is the protein druggable, i.e. have an area that will bind to a small molecule that would inhibit it or will you need to target the pathway upstream by targeting the mRNA. The latter is done with small interfering RNA molecules that causes the message for the protein production to be broken down by another enzyme called dicer. I could go but will stop here. I hope all this makes sense."

Epub: Agrawal et al. Extracellular matrix metalloproteinase inducer shows active perivascular cuffs in multiple sclerosis. Brain. 2013 May 17.

Background: Inflammatory perivascular cuffs are comprised of leucocytes (white blood cells) that accumulate in the perivascular space (spaces around blood vessels) around post-capillary venules (blood vessels where white blood cells across into the brain) before their infiltration into the brain and spinal cord. Inflammatory perivascular cuffs are commonly found in the central nervous system of MSers and in the animal model experimental autoimmune encephalomyelitis (EAE). White blood cells that accumulate in the perivascular space secrete enzymes (matrix metalloproteinases) that aid their migration into the nervous tissue. The enzymes digest the proteins around the white cells allowing them to tunnel their way into the brain tissue. 

These investigators' described previously that the upstream genetic inducer for the production of these enzymes (matrix metalloproteinase), the so called extracellular matrix metalloproteinase inducer, or CD147, is elevated in EAE, and that inhibiting this inducers reduces white cell entry into the central nervous system. 

Objective: In this study the investigators' investigated whether the extracellular matrix metalloproteinase inducer varies with the temporal evolution of lesions in EAE and whether it was seen in MS lesions, and whether it was a feature of inflammatory perivascular cuffs in MS lesions. 

Results: In EAE elevation of extracellular matrix metalloproteinase inducer was correlated with the appearance and persistence of clinical signs of disease. In both mouse and human samples, extracellular matrix metalloproteinase inducer was detected on endothelium (the lining of blood vessels) in healthy and disease states but was dramatically increased in and around inflammatory perivascular cuffs on leucocytes (white blood cells), associated with matrix metalloproteinase (enzyme that affects structural proteins) expression, and on resident cells including microglia. Leucocyte populations that express extracellular matrix metalloproteinase inducer in MS lesions included CD4+ and CD8+ T lymphocytes, B lymphocytes and monocyte/macrophages. The extra-endothelial expression of extracellular matrix metalloproteinase inducer was a marker of the activity of lesions in MS, being present on leucocyte-containing perivascular cuffs but not in inactive lesions. By using a function-blocking antibody, we implicate extracellular matrix metalloproteinase inducer in the adhesion of leucocytes to endothelial cells and determined that its activity was more crucial on leucocytes than on endothelium in leucocyte-endothelial cell engagement in vitro. Extracellular matrix metalloproteinase inducer activity regulated the level of alpha 4 integrin (the target for tysabri) on leucocytes through a mechanism associated with nuclear factor κB signalling. Blocking extracellular matrix metalloproteinase inducer attenuated the transmigration of monocytes and B lymphocytes across a model of the blood-brain barrier in culture. 

Conclusion: In summary, we describe the prominence of extracellular matrix metalloproteinase inducer in central nervous system inflammatory perivascular cuffs, emphasize its dual role in matrix metalloproteinase induction and leucocyte adhesion, and highlight the elevation of extracellular matrix metalloproteinase inducer as an orchestrator of the infiltration of leucocytes into the central nervous system parenchyma.


This is further fine detail of the mechanism by which cells get out of the blood and into the brain. It could be a target for a new therapy but as it acts like natalizumab it will be difficult to push this off its perch unless blockade has a better safety profile.

6 comments:

  1. It's a Bank Holiday, so can the above be simplified please for Lay People like me.

    Regards as always.

    ReplyDelete
    Replies
    1. "This highly technical paper explains that the migration of white blood cells into the brain and spinal cord of MSers is controlled by a protein that activates the production of enzymes that white cells use to tunnel their way into the brain and spinal cord tissues. By blocking this regulator, with a drug, you could potentially block migration of white cells into the brain and spinal cord. Is this important? Yes, we already know that blocking white cell entry into the brain and spinal cord is a very effective treatment for MS; this is how natalizumab or Tysabri works. This study describes another way of doing this. I assume Big Pharma are on the case already. How exactly you would do this is beyond the scope of this article, but is very complicated. Is the protein druggable, i.e. have an area that will bind to a small molecule that would inhibit it or will you need to target the pathway upstream by targeting the mRNA. The latter is done with small interfering RNA molecules that causes the message for the protein production to be broken down by another enzyme called dicer. I could go but will stop here. I hope all this makes sense."

      Delete
    2. Andy you are an expert but i bow to prof G

      Delete
    3. Hi All,

      Just catching up and thanks for the response. Not sure it helps a great deal ;-)
      I'll keep reading till some more of it crosses my brain barrier.

      Regards as always.

      Delete
  2. Although I didn't make the original comment, I want to thank you for responding as you have on a sunny Bank Holiday - almost as elusive as the answers you are searching for :-)

    ReplyDelete
  3. What is the nature of the matrix metalloproteinase inducer? Is it an endogenous protein upregulated in a signalling cascade? Or is it derived from an infectious agent? Breakdown of the extracellular matrix seems to be central to CNS inflammation. Can we learn from other neuro-inflammatory diseases whether infectious or non-infectious? Lots of questions. Interesting article - thanks.

    ReplyDelete

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