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Prevailing medical wisdom says that multiple sclerosis is an autoimmune disease - a disease in which the body's immune system turns in on itself. Specifically, it attacks the myelin sheaths that insulate the nerve cells in the brain and spinal cord. This immune system activity produces inflammation similar to what happens in the skin when we get a pimple.
Crucially, the inflammation also kills the cells responsible for producing and maintaining the myelin. These cells are called oligodendrocytes and they have long been known to die in large numbers during attacks of MS.
The majority of existing treatments for the disease and a fair proportion of new treatments currently in research focus on reducing the inflammation or disabling the immune system cells responsible for it.
However, a dramatic piece of new research published in The Annals of Neurology threatens to turn this understanding of multiple sclerosis on its head.
The study examined twelve brains of people with multiple sclerosis, concentrating on newly forming areas of disease activity called lesions. It found that the oligodendrocytes in these lesions were dying before there were any signs of inflammation.
This implies that it is not the inflammation that causes the death of the oligodendrocytes in multiple sclerosis but the other way around. The inflammation occurs in response to the oligodendrocyte cell death.
The authors, Michael Barnett and John Prineas of the Institute of Clinical Neurosciences at the University of Sydney, Australia don't deny that the inflammation might cause some of the damage seen in multiple sclerosis but they do paint a radically new picture of of the disease.
They suggest that the first stage of the development of a new multiple sclerosis lesion is mass suicide of the oligodendrocytes over a relatively small area. This process is called apoptosis or programmed cell death and is a normal response in the human body during growth and repair. If cells were allowed to grow and divide without limits, they would form a cancer. Similarily, cells infected by viruses or cells that are no longer needed by the body will often cell kill themselves.
Barnett and Prineas observed oligodendrocytes in which the central nucleus was shrivelling up - a typical sign of a cell committing suicide. Other cells in the brain were also changing. Microglia, another type of maintenance cell which can swallow up dead and dying cells, were forming long extensions ready to engulf the dead and dying oligodendrocytes. Additionally, a group of proteins, called complement, which are responsible for activating the body's rubbish-collecting cells, had collected on the myelin. Crucially, the rubbish-collecting cells of the immune system, the macrophages, had not yet appeared in the lesion.
Within one or two days of lesion formation, all the oligodendrocytes had disappeared. The authors suggest that they had been swallowed up by the microglia. The spaces that they had once occupied were now full of liquid forming what is known as edema.
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The next stage seems to be the invasion of immune system cells. Macrophages now start to appear, together with T cells, the orchestrators of the immune response. These initiate and take part in inflammation. The macrophages start to gobble up the myelin left over by the vanished oligodendrocytes.
The final stage would appear to be regeneration. Oligodendrocyte precursor cells, cells that have the ability to develop into new oligodendrocytes, move in to replace the lost cells. They are fed special chemicals called trophic factors by the macrophages and the process of remyelination can begin.
It is important to bear in mind that this was a study of only 12 brains and further work needs to be done to validate the studies findings. However, if this work reflects what is actually happening in multiple sclerosis, then its implications are earth shattering:
Multiple sclerosis will no longer be an autoimmune disease. A lot of text books are going to have to be rewritten.
Treatments that target inflammation will not not addressing the root cause of the diease. This does not mean that they are not effective to some degree but that they can never be as good as treatments that target the death of the oligodendrocytes.
All the animal models of multiple sclerosis are poor representations of the disease in that they are all primarily autoimmune models. Perhaps this is why so many treatments that are so effective in mouse models prove to make no difference to multiple sclerosis in humans. For animal models to be valid, they would need to show the kind of disease process described by Barnett and Prineas.
Researchers will need to change direction. Whilst work on oligodendrocyte precursor cells becomes more important than ever, work on describing the inflammation process in multiple sclerosis needs to take a back-seat. Importantly, researchers need to find out why oligodendrocytes are dying and what can be done to stop them. Quite how the world of multiple sclerosis research will react to this paper is unclear. Thus far, Barnett and Prineas's paper seems to have been met with a deafening silence which is why I decided to write this piece.
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