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Acquired Immunity
Written by Tim Sheppard MBBS BSc. Last updated 9/11/10

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What is acquired immunity?

Acquired immunity is the kind of immunity which is not innate - it's the ability to fight off infections which you couldn't do when you were born. There are various systems in the body which are set up to get rid of bacteria and viruses automatically - natural killer cells, for example. These use certain features of bacteria and virus invasion to get rid of them before they become a problem. However, some of these have particular ways of getting round the body's innate defences, and it can also be risky to have just this general system in place.

The body has been specially designed to have several mechanisms of attacking specifically those threats which is recognises - and a large part of this requires recognition of an antigen.

What is an antigen?

An antigen is just a protein with a specific shape which you'll often find on the surface of a cell, which will be recognised by the body as foreign. That means the body recognises these proteins are not produced inside the body, but rather must have come from another source - a virus or bacteria, for example. Strictly speaking the protein doesn't have to be on the surface, but I tend to find it helpful to think of them like this. Because they are foreign, they will cause B-cells to produce an antibody, specific for that antigen shape, to try and fight off whatever brought it into the body.

Rather confusingly, the human leukocyte antigen system is a range of proteins which are actually not foreign, but are used to present proteins which are.

What is the major histocompatibility complex (MHC)?

The MHC is a whole set of genes which code for proteins which are involved in presentation of antigens. In humans this system is known as the human leukocyte antigen system or HLA system, but it is often subdivided into class I and class II MHC molecules. These MHC molecules are a bit like billboards, and it is upon these that antigens are presented for other cells (particularly T-cells and B-cells) to see.

MHC Class I molecules are present on all nucleated cells. These will present proteins that are produced by the cell, so normally this just shows that the cell is 'self' (that is, that this cell is produced by the body and is not a foreign bacteria or something like that). However, it a virus gets into a cell, it will start producing foreign antigens which will then be presented on the MHC class I molecules and recognised as foreign by cytotoxic T-cells.

MHC Class II molecules are present only on antigen presenting cells. Antigen presenting cells will chew up something that they have gobbled up, and then present the fragments on the MHC II molecules for T-helper cells and B-cells to recognise.

What is an antigen presenting cell?

An antigen presenting cell (APC) is a cell which, unsurprisingly, presents antigens. This means that it contains a molecule on it's surface upon which it presents the antigen so that other cells (particularly T-cells and B-cells can see it). This surface molecule is called an MHC Class II molecule, and it's a bit like a bill-board. The poster on the bill board is the antigen, which the APC presents to help out with the whole process of acquired immunity.

The APC gobbles up some bacteria or something like that, and chews it up to produce lots of protein fragments. These are kicking about inside the APC, so it decides to present them for other cells to see, and it sends them up to the surface and presents them on the MHC class II. If a T-helper cell happens to be passing, and it has a T-cell receptor which is the right shape for the antigen which the APC is presenting, then it will activate it. The same is true of a B-cell.

How does the body respond to a foreign antigen for the first time?

So, something like a bacteria invades the body. Perhaps it gets in through a cut in the skin. It has the potential to cause big problems because it can disrupt the processes which each cell in the body goes through.

First things first, then - phagocytosis. The invading pathogen is gobbled up by a specialised cell, and broken down into smaller fragments - into lots of proteins, generally. These antigens are then presented on the surface. You've guessed it, it's an antigen presenting cell, and its displaying it's prize catch for all to see.

This isn't some kind of cellular pride, but rather an opportunity for a T-cell to notice something's going on. Although this is the first time that the bacteria has appeared in the body, T-cells have already been made which will recognise the antigens that are presented. The reason that the body has not got an innate resistance to this bacteria, however, is that there aren't many of these T-cells. As far as the body knows, they're never going to be used. The body is producing millions and millions of T-cells, and altogether their T-cell receptors will be able to recognise pretty much any antigen which appears in the body. The things is, you're not going to find every antigen invading your body - not all of them are used by bacteria.

So, when an antigen presenting cell presents an antigen which does actually belong to a bacteria, it's basically saying to all the T-cells, 'Look, this really is a real antigen - it's something we actually do need to respond to!'

A CD4+ T-cell will make an appearance - and, if it's the right one, it's T-cell receptor will fit in nicely with the antigen being presented on the MHC II molecule.

The T-cell also needs co-stimulatory molecules - other molecules which are present on the APC's surface which confirm that this is indeed a threat, and something we need to respond to. These interact with molecules on the T-cell's surface, and cause it to become activated.

Activation of a CD4+ T-cell has two major effects; one is that the T-cell starts producing a molecule called interleukin-2 (IL-2), the second is that the CD4+ T-cell turns into a mature T-helper cell.

Production of IL-2 is a self-perpetuating process. IL-2 actually stimulates the CD4+ cell itself - it causes the CD4+ T-cell to produce yet more IL-2, and the more it produces, the more sensitive it becomes, so the more it produces. It is an example of a positive feedback loop.

The other thing which IL-2 does is that it stimulates CD8 cells. Now, if IL-2 were simply to cause every single CD8 T-cell to become activated, we'd have a bit of a problem, because the CD8 T-cell, when activated, becomes a cytotoxic T-lymphocyte, which means that it will cause cell death - and we don't want every single T-cell to be going around killing everything; we just want those that will fight our original bacteria.

So IL-2 is one of the things which will cause the CD8+ T-cell to be activated. The T-cell also needs to be in contact with an antigen presented on an MHC Class I molecule - which is something that our dear friend the antigen-presenting cell can sorted out for us. While MHC II molecules are only present on APCs, MHC I molecules are present on every single nucleated cell, so that includes APCs.

So, when the CD8+ T-cell finds an MHC Class I molecule presenting an antigen which fits its own specific T-cell receptor, and when a CD4+ T-cell nearby is producing IL-2, the CD8+ T-cell will become activated.

So what in practice does that mean?

Well, now this newly activated cytotoxic T-lymphocyte (CTL) will shoot off around the blood stream, and if it finds a cell presenting the foreign antigen that was involved in its activation, then it will bind to the cell presenting the antigen and produce perforin and granzymes.

You may think that these don't sound like particularly friendly chemicals, and you'd be right. These are what the CTL produces to kill the infected cell. This is particularly relevant for virus infection, since normal nucleated cells will often have their systems invaded by a virus. The proteins produced in the cell will be presented on MHC I molecules, which will enable CTL's to spot which cells have been infected by the virus - and, having been activated previously at the APC, they're prepared to do their worst.

Now the particularly observant among you will have noticed that we've not completely finished the story. The activation of CD4+ lymphocytes leads to production of IL-2 (and hence the activation of CD8+ lymphocytes), but it also leads to the development of CD4+ lymphocytes into mature T-helper cells. So why would you want that?

One of the most important things that the body does to fight off infection is to produce antibodies. These help to neutralise the invading virus or bacteria by binding to the parts which would otherwise threaten the body. They can also alert the immune system to the fact that a foreign antigen is there so that cells such as natural killer cells and neutrophils can attack it and get rid of it.

Antibodies are produced by plasma cells, which develop from activated B-cells. B-cells are activated in a similar way to CD8+ T-lymphocytes, as they are activated by cytokines (e.g. IL-4, IL-6) produced from T-helper cells.

B-cells will bind to antigens presented by APCs in a similar way to T-cells - with a specific receptor that will only recognise an antigen with a specific shape. This time, however, the B-cell takes in this antigen and presents it on its own surface, on an MHC Class II molecule.

This enables the T-helper cell to recognise it - and, with some co-stimulatory molecules (CD80/CD28, CD40/CD40 ligand) kicking about, this stimulates the T-helper cell to produce chemicals which will activate the B-cell.

The B-cell then turns into either a plasma cell (which will produce antibodies against the antigen until it can't find any left) or a memory cell (which will kick about in the blood stream for years, waiting for the antigen to appear again).

How does the body respond to a foreign antigen from then on?

It may seem like an incredibly elaborate and over-the-top mechanism for attacking and ridding the body of some virus or bacteria. But in actual fact it is very clever indeed, because the way in which the body responds to a foreign antigen for the first time enables a better response in the future.

Consider that before we got started, there were hardly any T-cells and B-cells, and it took quite a while for them actually to become activated. Now, since T-cells and B-cells can produce memory cells after being activated, these will become activated much more easily - and there's a lot more of them hanging about.

When an antigen appears for the first time, it shows the body that this particular antigen is relevant, and so the body produces a whole load more of the cells which will combat it. So, when it makes an appearance a second time, a much stronger line of defence has been built up ready to face the threat and fight it off.

If an antigen makes another appearance, the body's development of acquired immunity means that T-helper cells, CTLs and B cells can target the pathogen quickly and easily, activated immediately and with more of them activated.

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