Espresso Pathology: Lesion formation
We recently looked at different cell types that make up the brain tissue, now we see how they are involved in, and are attacked during multiple sclerosis.
A pathologist (someone who studies disease) such as myself or Doctor PowL will look at brains from MS'ers. You can often see evidence of MS with the naked eye by the development of MS plaques (MS lesions), which are areas of scar tissue (circled in yellow).
These are easy to see in the white matter
(bit of brain tissue containing the nerve tubes/axons
). However, they also occur in the grey matter
(bit containing the nerve cell heads) on the outside of the white matter in the brain but on the inside of the white matter in the spinal cord.
The grey matter on the outside layer looks grey and the white matter is inside this
However, to see a lot more pathologists must look down a microscope and stain the different cell types with specific dyes so that we can see them. If we make a slice through the brain of spinal cord and look in the white mattter, which contains the nerve axons (in red). This is surrounded by myelin (green). This tissue would contain oligodendrocytes, astrocytes and microglia but we haven't added them as it will make the picture look a bit messy. In the magnetic resonance imaging (MRI) scanner you can't see anything abnormal.
The lesions of MS are typically concentrated around small veins (venules) and a single vessel has been highlighted (white edges) above. Although there may be other explanations we believe the first event of MS is due to a problem with the oligodendrocyte (could it be that it is being infected with a virus or are these cells stressed? Although some of you may think this is a problem caused by the vasculature abnormality, evidence of this is relatively lacking). This damage is spotted by the microglia, which become activated. We call this the pre-active lesion. There we can see clusters of microglia (brown cluster below) and often oligodendrocyte damage (loss of myelin).
There lesions may resolve (get better), but when the microglia become activated they can secrete molecules that will trigger the lining of the blood vessles to produce molecules (Flags) that can be seen by passing white blood cells that tell them to enter the blood vessel. This occurs in venules (small veins that carry blood from the tissues to the heart) because this is where the blood pressure from blood flow is lowest so it is easy for the white blood cells to slow down and stick to the blood vessel wall.
The white cells push their way through the blood vessel cells (endothelial
cells) and form a perivascular cell cuff (picture on right shows white blood cells around a blood vessel) around the blood vessel and this can be seen as Dawsons fingers
when they occur around the ventricles (fluid filled space in the brain). At this stage they haven't entered the brain tissue but as they are kept within the glia limitans
which is a membrane formed by the foot processes of astrocytes that are present below the blood vessel wall. In MRI (there are two obvious lesions at one and nine o'clock and probably another a 4 o'clock relative to the position of the brain in the example below) this can be seen as a gadolium-enhancing lesion and is known as an active lesion
. The cells in there lesions are often lymphocytes (white blood cells known as T and B cells) and macrophages. Granulocytes
are less common. This suggests that there in an immune problem in MS and is consistent with the finding that the genes that have been linked to susceptibility to MS are associated with the function of the immune system.
The cells then burrow through the glia limitans and enter the parenchyma of the brain (brain tissue) and the macrophages are a common feature and they eat the myelin debris as they expand outwards from the original vessel. This will cause further nearby blood vessels to leak such that the MRI can see a ringed structure (lesion at 1 o'cloc in the picture below) behind a quiescent centre of the lesions. This is called chronic active lesion. There is a dense region of macrophage activity at the lesion rim and the macrophages are full of lipid droplets because they are eating the fatty-myelin sheath (red stuff is lipid in the right-hand bottom picture below).
MS lessions expand for about two weeks to a month and then the immune response is down regulated by some poorly understoood mechanisms and the white blood cells dissappear and probably die in the brain. The appears to be two paths followed after this, either the oligodendrocytes enter the lesion and start to make new myelin known as remyelination. If remyelination does not occur then nerves may be vulnerable to damage and loss. You can see the myelin sheath (black bit surrounding the nerve in the top left picture below). Demyelination in top right picture (note the black ring in missing). Remyelination (bottom left) is seen by the return of thin-myelin sheaths. Bottom right is a fluid filled space where nerves used to be indicating nerve loss.
Once the immune response is silenced, if the damage is not repaired then astrocytes (yellow cell) enter the lesion and form a scar. This is then difficult to repair via remyelination. This leaves a demyelinated lesion that is called a chronic inactive lesion. This may represent a MRI black hole (one o'clock in MRI image below).
The aim of MS researchers must be to repair the myelin, we need to instigate Prevent MS
to stop the the disease from starting. Once it has started we need to stop the white blood cells from getting into the brain to cause damage. We are getting increasingly better at this.
We need to stop nerve damage from occuring once the immune system gets in the brain and we have started to do this to treat MS, then we need to repair the nerve damage. Unfortunately we are at early stages in the investigation of this form of treatment aim.Next time we will look at lesion variation, which suggests that there could be different triggers, or is it similarity?