Immunity

When I was 13 and studying chemistry for the first time as a serious science subject, like many in my class I found the seemingly infinite number of chemicals and the formulae we had to learn exhausting. But it was not unwieldy because after a while, although there were always new chemicals to learn, familiar ones like CO₂, H₂O, HCl, started recurring, making it manageable. Then the next year we came across organic chemistry where infinity was the right word. The number of organic molecules and substances was truly daunting, especially as we progressed to polymers, which like the infinite list of counting numbers, could go on forever by simply adding one more unit.

Much later on as I passed through higher studies of biochemistry and then to medicine, I became fascinated by the human immune system. Specifically its ability to create an antibody to essentially any antigen that invaded the body. Most people understand that it is some of the biochemical material of the invader that is the antibody and it is some other biochemical that our bodies produce in reaction that is the antibody. How could a system create what is a bit like an antidote to a toxin for an infinite number of potential invaders, none of which can be anticipated in advance, so which are always a surprise and a shock to the system? But it comes up with a solution. Remembering also that pathological organisms like bacteria and viruses are being created or altered all the time, so your body sometimes gets invaded by some organism that never existed before. Yet your immune system still creates an antibody to neutralise it.

And it gets more interesting. As I learned in biochemistry, the organic building blocks in all living things are basically the same. We all have proteins, carbohydrates, lipids, nucleic acids and so on. The amino acids in a bacteria’s proteins are the same amino acids in ours, and the sugars in a polysaccharide are the same in every living thing. And it is those chemicals that are used as signals to our defences to eliminate the intruder. If the same basic molecules in us are in an invader, how does our immune system know “us” from “them”? A lysine amino acid in our proteins is exactly the same lysine as in a bacterium’s for instance? It is truly amazing.

It amazed everyone, until the mid 1980’s when a Nobel Prize was awarded to Niels Kaj Jerne, a scientist who along with others, working a decade earlier figured it all out. He even spent time at the University of Pittsburgh which is in a city I love. And true to form, his theory was received with scepticism initially. It turns out that the immune system, along with the genes and chromosomal system and the human neural system, is one of the most complex systems in nature. It is so complex, with so many parts to it that do the work in different ways, and we are still discovering it, that I only want to talk about a small part of the system. This so called adaptive immune ability. It is only found in vertebrates.

The answer goes back to those seemingly infinite number of organic chemicals. Look at sugars for instance. We are familiar with sugar. If you are like me, you prefer 6 spoons in your coffee (well when I was 19 perhaps). Some of us might know that a sugar is also called a saccharide, and know roughly in a chemical sense what it is. It is a short string of carbon atoms with a mix of hydrogen and oxygen atoms attached. There are two hydrogens for every oxygen, the same ratio as in water, hence sugars are called carbohydrates. The string, or chain, can be any length, but is typically 5 (pentose) or 6 (hexose) carbon atoms long. There are 3 and 4 and 7 and 8 and more, but none past about that. Instead of an infinite number, there are only about 500 possible sugars with a chain of 6 carbons for instance. Suddenly this looks manageable. 500 is a big number but far from infinite. The infinity part only emerges when many of these small sugar molecules are hooked together to form polysaccharides. Common table sugar, called sucrose, is a disaccharide, a string of just two sugars linked together, glucose and fructose, a hexose and a pentose. Imagine linking thousands of the hundreds of different sugars together randomly.

Same with nucleic acids (in chromosomes), and with amino acids. Amino acids for instance are the building blocks of chains which when long are called proteins and shorter ones called peptides. There are again about 500 amino acids found in nature, but only 22 are fundamental to proteins, a very manageable number. Proteins though are the most common material found in living things and they can be tens of thousands of amino acids long, mixed in any order, so an infinite number of possible proteins. The complexity, and the complexity of the challenge to an immune system, returns.

So what happens? It all starts with the invader. Molecules or parts of a molecule from the invader are called antigens. So an antigen is one of those chemicals, but only called that when it is capable of combining with a special protein in your body called an antibody.

Dealing with the complete, infinite, clearly unrecognisable macromolecules would be impossible. That was the original puzzle. But if we break the macromolecule apart, to its component parts, suddenly we have a much smaller number of standard parts, amino acids, sugars, and so on. But that would not help because they are the same parts as in us. Reacting to them would also result in reacting to our own tissue. In fact this is similar to what happens in an autoimmune disease like rheumatoid arthritis. But it is part of the answer because each of those subunits has a unique shape and it is possible to make a matching negative image of the shape, in that familiar lock and key metaphor, so that the negative which is called a coreceptor can connect to the positive. The chemical binding potential within this pair can be extremely strong. A bit like a magnet picking up iron filings.

Now if instead of breaking the large macromolecule, the protein, the starch or the fat or DNA or whatever, from the invader into all of its small units, we break it down partly only, to result in say a peptide (not an amino acid) or an oligosaccharide (not a monosaccharide, oligo means a few) then we start to get small combinations of units in a different combination from anything in our body. It’s like breaking down a brick wall. You could separate every single brick. Then a brick is a brick is a brick and no different from any other brick. But break the wall down so that several bricks are still connected together, then funny odd shapes start to appear. Like random Lego blocks stuck together or the shapes in a Tetris game. And each of those small pieces are composed of a small number of recognisable parts. The process is called antigen presentation and processing.

Now it is possible to make a mirror image, a coreceptor, to match that funny shape. That is done by having available, all the hundreds (but not infinite) single coreceptors, and joining them up randomly, thousands of combinations but still not infinite, so that hopefully one matches the antigen. That final process occurs in another complex system where a giant immunoglobulin in your blood cells has the coreceptor on its end, ready like an angler to locate and snatch antigens. That is the actual antibody with its binding site.

Once a molecule has been found and binds to the coreceptor, it is inactivated, so can do no damage. Like if a nut is permanently stuck in the end of a spanner, the spanner becomes useless. Special blood cells remove the inactivated combo and in turn those cells are disposed of, coming out of your body as pus. Yuck! But the appearance of pus means the system is at work.

That process is ongoing all the time, and thousands of these random coreceptors exist in your system all the time. Just floating around. When one becomes useful because suddenly there is an invader and a match is made to the antigen, that particular one gets multiplied massively, and you have the means to fight off the invader. It takes a little while for the amplification process to get up to speed, a week or so, so you are very ill from the infection for that period, but then you get out of bed again, exhausted but well, the crisis over. Making all these chemicals takes energy, similar to running a marathon, which is why you are exhausted, and why you should “feed a cold”.  I always eat tons of ice cream and chocolate. Any excuse.

Afterwards, those large numbers of useful antibodies hang around for a long time, providing instant immunity if that particular virus or pathogen infects you again. It has a memory. We get a tetanus booster every 10 years or so, because that is how long your system continues to keep large numbers of tetanus antibodies around. It is also why we rarely get a second infection. It can actually happen, but we instantly irradicate it because we have the weapons, so you may even be unaware. And if you can isolate the antibody and clone it, then you can inject them into someone else to give them instant immunity. Monoclonal antibodies.

So how does the original invader, with all of its macromolecules get broken down so this process can take place? A separate and evolutionary older immunity system called the innate immune system, which also exists in plants and fungi and invertebrates, does that. It is not adaptive. But don’t be misguided, it is very complex also. It comes with some predefined detectors of the most common or most expected antigens. Those from evolutionary experience, the species’ history, which are most likely to be present in an invader. That works for the most part, but fails for complex pathogens that can change their chemistry to trick your system. In vertebrates, part of that innate system does the breaking up and passing of the funny partial shapes over to the adaptive immune system.

A final bit of discussion. One way an organism knows which cells it encounters are its own is because of signature protein molecules on the outer membrane of the cell. Different for every individual just like finger prints. A species has a class of these cell surface antigens, so all humans for instance have their species specific types, like all humans have fingerprints even though they are different from each other. So if your immune system encounters cell surface antigens that are not its own, it attacks that cell. There are 48 different cell surface antigens known, and the stronger ones are familiar as the blood groups ABO and Rh (also referred to as D) systems. Unfortunately it is that immunity protection that prevents us from accepting an organ donation from another person even though they are humans.