The immunology of multiple sclerosis
Alasdair Coles, Wellcome Fellow in Neurology, Addenbrookes University Hospital NHS Trust
Way Ahead 2003;7(2):4-5
Beware anyone who claims to understand the immunology of multiple sclerosis. They do not. It is a mystery. Partly this is because multiple sclerosis is a difficult disease to unravel. And partly it is because the immune system is incredibly complex and not well understood. Just think what it does every second of every day. It continuously patrols the body, leaving well alone what should be there, but recognising instantly anything 'foreign' and then getting rid of it. And most of the time, even in people with multiple sclerosis, the system works brilliantly. Full scale viral attacks are dealt with in a matter of hours and days, bacterial infections may be longer. And all the while that the immune system is aggressively clearing out these predators, the rest of the body is untouched. If only identifying and destroying weapons of mass destruction were so easy.
Meet the team
Blood is composed of red cells, which carry oxygen, and white cells, which are part of the immune system. White cells are divided into several different types and, for fun, given bizarre names like 'eosinophils'. The ones we are interested in are called lymphocytes. You may know these better as 'B cells' and 'T cells'. B cells produce antibodies and secrete them, to float about in the blood and latch onto bugs to help get rid of them. These cells are stimulated when you have a vaccination. T cells are a little more complex. One type of T cell acts as the B cell's partner in ejecting bugs, not by producing antibodies, but by nuzzling up to cells infected with virus and gobbling them up. These T cells are called 'CD8 cells' (there is - sort of - a point to these 'CD' names but only just). There is another type of T cell called ...
...the lazy manager: the "CD4 T cell"
We all know office managers who are slightly officious and just a little lazy. The CD4 T cell is like that. Its job is to decide, as it sees little particles of this and that, whether they are part of the body (and therefore to be ignored) or part of an invading bug (and therefore to be attacked). It is not a proactive type of manager. It sits in its office (otherwise known as a lymph node) and waits for proteins to be brought to it by other cells, called 'antigen presenting cells'(would that be a secretary?) (See Figure 1). It then contemplates the particle and decides what needs to be done. The CD4 cell does not actually dirty its hands by doing any of the work; it just orders other lowly cell types about (!). It does this by sending a stream of messages, in the form of secreted molecules called 'cytokines' that activate this cell, quieten down that cell, and generally get everything sorted.
The reason for dwelling on this is: if the CD4 cell gets it wrong, and identifies part of the myelin sheath of nerves as an invading bug, then there will be an immune attack on myelin. So, perhaps, multiple sclerosis is a disease of 'mistaken identity'. How might this happen?
figure 1
Crossed wires in the immune system
The CD4 cells are incredibly fussy. They insist that the particles they are shown by the antigen presenting cells are bound to a specific molecule called - more jargon - 'Class II' (Figure 1). Now these Class II molecules are different in each person. In fact, they are the same molecules that create all the problems with rejection in organ transplantation. All the palaver of tissue-typing for transplantation centres on getting the best match of Class II molecules. The consequences of this for multiple sclerosis are shown in Figure 2. Essentially, to the immune system of one person, a virus may mimic myelin; yet the same virus may appear completely different from myelin to the immune system of another person. Thus, one virus may cause multiple sclerosis in one person yet be completely harmless in another. The difference between them is their Class II molecule. As proof that this idea may be true in multiple sclerosis, consider this: for all the millions of pounds and man-hours spent analysing the genetic causes of multiple sclerosis, only one thing has been established clearly: that the risk of getting the disease depends on the type of Class II molecule you have. (The jargon for the genes controlling the Class II molecule is HLA). This concept also explains why searching for one virus as the cause of multiple sclerosis is misguided. For the same virus may have completely different effects on the immune system depending upon the type of Class II molecule people have.
figure 2
Step 1
Step 2
This is what happens when person A and person B are infected with the same virus. The CD4 cell sees different parts of the particle with the different Class II molecules. In both cases the immune system mounts a defence against the virus.
Step 3
Now look what happens when these same CD4 cells see myelin particles. With person A they are recognised as different and left alone. But in person B, myelin looks like tghe invading virus, so the immune system attacks the myelin.
A meningitis-multiple sclerosis mix-up
Once this mistaken identity occurs, there are CD4 T cells that think that myelin is an invading bacteria or virus. That is very bad news. These rogue T cells become activated. Finally the manager leaves the office and starts to do something. The activated rogue T cells patrol through the blood vessels throughout the body, looking for their target. Because they are activated, they can squeeze through the blood-brain barrier (this is not true for inactive T cells) into the brain. There they find their goal, an invading bug as they see it. They call in the troops (using cytokine messages) to destroy the bug, just as you hope they would if you had meningitis or encephalitis. Only in this case, the invading virus is not a bug but is myelin. So all the forces that normally work to our advantage in defence are then unleashed on our delicate brains.
A health warning
To be honest, this is an over-simplification. It does not explain a lot of what we know about multiple sclerosis and it may turn out to be wrong. Beware anyone who claims to understand the immunology of multiple sclerosis. They do not. It is a mystery.
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