Jonathan Edwards
"Gibberish"
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My colleagues and I are putting a lot of thought into just this. Maybe one could also ask why is it that Manchester United tend win at football when they have exactly the same number of team members as other teams, yet even so, over the years their success goes up and down?
It seems that the immune system has certain fairly fixed rules about how many B and T cells it can find space for. These numbers do vary from person to person but probably not enough to matter much most of the time. What matters is the combination of very specific skills belonging to each cell and the ability of the cells to 'pass the ball on' to players further up the field in a co-ordinated strategy that fools the enemy. Things like viral antibody titres or ANA can tell us about specific skills in a very crude way but we have absolutely no way to measure the team strategy. And it is likely the team strategy will be constantly evolving partly as old players retire and new ones appear and partly because old players become the team selection panel - some very good at that and some not.
I will stick to B cells because T cell populations are probably much more stable after adolescence. B cell populations are constantly being replaced. So, what do I mean by cells 'passing the ball on'? Each B cell makes a unique shape of antibody. That antibody can bind to a wide range of antigens or it can be specific for just one. It can bind strongly or weakly. For any microbe protein antigen there may be twenty main surface patches or 'epitopes' that an antibody can bind to. The antibody can bind to its epitope from left side or right side, sometimes getting in the way of another antibody binding and sometimes not ... The possibilities go on for ever and I haven't even mentioned the four classes of secreted antibody, the four IgG subclasses and the variants in framework region that can have extra binding sites on them.
When an antibody binds to antigen it always tends to generate both an amplification signal and a turn off signal. Antibody bound to antigen can amplify further antibody production by ticking up other B cells that recognise an epitope on the other side of the antigen. But if all the antigen epitopes are covered in antibody it becomes invisible and the system is turned off. Turning on and off also depends on whether antibody clumps antigen molecules together in pairs or large groups - which also feeds in to whether you get inflammation.
It seems that, quite remarkably, the B cell system has rules that make sure we usually end up with a 'sensible mixture' of antibodies with all skills - some solid defenders that recognise all comers, some mid field players to link up and some strikers who can hit a precise point in goal from any distance. But one can imagine that it would be likely that the team make up would gradually shift with time. The more infections we see the more highly specific antibodies we are likely to make. We might end up with a team full of strikers. Blood tests would show nothing different. We would be very good at not getting a second dose of a strain of 'flu' but might have no defence against Ebola.
I suspect that all of us do see an evolution in our antibody responses in adulthood. There are also evolutions in antibody responses in whole populations. Native South American populations have no experience of flu and so often die if infected as adults. I have only once had a cold with a really blocked up gummy nose in the last twenty years. I have had quite a few sneezings and sore throats and sinus pains but not a gummy nose. I have a theory about this, which is that the traditional gummy nose cold was actually caused by cloth handkerchiefs spreading viruses that made gummy noses that were blown on to handkerchiefs and pulled out of pockets all day long and infected ... Now that we use tissues viruses that cause gummy noses have a much harder time.
So the basic idea is that the exact make-up of antibodies with specific skills in our bodies is probably always changing and it might not be surprising if for a period of years (long lived plasma cells making antibody last up to about ten years) the selection panel might shift the balance one way or another. Moreover, because the ball passing needed is so complicated it would not be that surprising if a team got stuck in a bad strategy like overdoing the cytokine response to every little virus that turns up. Some great football teams of the past have sunk down the rankings and got stuck there apparently simply because of selection panel strategies.
And none of this would show up at all on standard tests.
So how the heck could one test such an idea? The hope is that we can get a clue from looking at detailed features of what look like perfectly ordinary antibodies. One interesting thing is that in a number of autoimmune diseases antibodies are often made using a framework template that normal people have but virtually never use. Its a bit like trying to find out the political affiliations of a terrorist group not by looking at who they are shooting at but by looking for the manufacturer's name on the rifles.
