Almost everyone will have heard of antibodies, they’re the well-known good guys of the immune system, the knights in shining armour to the (dam)cell in distress, under attack from big bad viruses and bacteria. But not many people really understand what an antibody is or what it does, which is a shame because it is every bit as impressively awesome as you would imagine a molecular knight in shining armour to be.
Antibodies are proteins that bind to any incoming pathogens, including viruses, bacteria and other assorted baddies of the immunological world, with the intention of initiating an immune response. I always like to envision the cells and molecules of my immune system taking to my body as if it were a field of battle, mace-wielding macrophages dashing around engulfing and destroying invaders, battle-ready B-cells co-ordinating from the rear-guard. The way in which your body fights invading disease pathogens is the stuff epic fantasy novels are made of, and complicated enough to need a whole other post. But today is about the antibody, and how through molecular trickery, it guards your body like a true knight.
The key role of antibodies is to bind to antigens on the surface of invading cells; antigens are little molecular markers that allow the body to recognise invaders. Now, you may or may not believe in the idea of soul mates for people, but molecular soul mates definitely exist; each antibody is designed to bind to one antigen. Although, it has to be said, when it does meet its match, it doesn’t precisely wander off into the sunset holding hands and snogging, it’s actually more like finding your one true nemesis than your one true love. Obviously, in a system where each antibody is designed to bind just one antigen, you need to be able to produce an astonishingly wide range of different antibodies, with the ability to recognise an almost infinite variety of antigens in order to effectively protect yourself against as wide a range of invaders as possible. Particularly because some viruses, for example influenza and the common cold rhinovirus, mutate rapidly and constantly, meaning that they are constantly producing different antigens. Clearly, to combat this kind of molecular ninja behaviour, antibodies have to be something truly special.
Antibodies are beautifully clever, in fact they are more than that, they are biochemically stunning. They’re formed from four chains of amino acids, two light chains and two heavy chains, which are bound together in a Y shape. The binding site for antibodies to interact with antigens is at the tips of the two Y prongs, and no two are the same. The binding sites are formed from hyper-variable regions at the end of each of the four chains. It is this variability that allows them to recognise such a mind-blowingly wide range of pathogens, and they achieve this by a number of really clever molecular tricks.
First, each variable region is formed from three segments, V, D and J segments. Each person has multiple different types of each segment, and when I say different types, I mean that the segments are formed from amino acids which are arranged in a different order, like multi-coloured beads on a string, where a minor change in the order of the colours makes a difference. The difference between V-segment-1 and V-segment-2 may be as simple as swapping two colours around, but it is enough. When the antibody is being constructed, the molecular foreman in charge can use any one of a huge range of combinations of the three segments. For example you can have V1,D1,J1 or V1,D2,J1, or V5,D3,J4, and so on and so on. Already this provides a fairly large pool of different variable regions, all of which can bind different antigens. In itself though, this still isn’t enough. We’re facing a whole world of potential antigens; even hundreds of thousands of varieties may not be enough to recognise them all.
So, as well as the VDJ recombination, there is an additional process that allows for even greater variability. This process is known as somatic hypermutation, which very much sounds to me like the kind of thing used to generate superheroes, and actually that’s not so far from the truth, it does produce molecular knights in shining armour, after all. So, during the immune response, B-cells, which produce antibodies, are required to reproduce rapidly. During this reproduction, they naturally have to reproduce their entire set of DNA, including the DNA that contains the blueprint for the antibodies they produce. During the replication of the antibody DNA, tiny random changes occur in the antibody variable regions; these changes are equivalent to one single amino acid change, one single colour swap in the chain. Again, though, these tiny switches make a big difference, and lead to further variability in the binding regions. Any variation that proves to be good at binding to the specific antigen that is invading is recognised as being good at its job. It is suddenly produced in huge amounts, ready to rally the troops.
Antibodies are truly one of the wonders of the molecular world; their sheer variability is one of our body’s greatest defence mechanisms, and the truly stunning thing is that, as is so often the case in molecular biology, it comes down to such tiny, seemingly insignificant changes. If that’s not Really Awesome, I’m sure I don’t know what is.