What is a human's best defence against disease - doctors, choice of food, sanitation or the immune system? Without an immune system, it is highly unlikely that you would have survived long enough to be reading this article.

Briefly, the immune system consists of a series of defences that work together to stop infections from spreading - the complement system, neutrophils, macrophages, B-cells, different types of T-cells and 'Natural Killer' cells.

Knowing the 'Enemy'

Bacteria

Bacteria were living on this planet millions of years before humans and, in a way, are our ancestors. A bacterium is a unicellular organism: each bacterium is one cell. They do not have cell nuclei¹ and have a significantly different chemistry to human cells, which is the strategy behind anti-bacterial drugs. Bacteria are about two micrometers² in length - about 10 times smaller than one of our cells. Like most cells, a bacterium reproduce by cell division - the original cell divides into two cells that then grow to become exact duplicates of the original cell. In addition to this, bacteria can also exchange genetic information with other bacteria - bacterial sex - increasing the probability of mutation. Some mutations increase an individual bacterium's chance of survival, compared to other bacteria, and so allow it to produce more copies of itself than other bacteria can. Over time, only the more successful bacteria survive and, in this way, bacteria can evolve to become drug resistant.

The vast majority of bacteria are totally harmless to humans - most surfaces, including your skin, are covered by them yet people are not continuously ill.

Viruses

A virus is about a hundred times smaller than a bacterium, 10-100 nanometres³ long, and is too small to be seen under a light microscope. (This is because, due to the nature of light itself, the best light microscope can only see particles greater than 200 nanometres long) It is composed of genetic information and a protein coat. A virus particle, before it has infected a cell, is often referred to as a 'virion'. The virus's genes encode the proteins needed to form the protein coat and some proteins that enhance its replication. A virus cannot replicate on its own - in order to do so it has to infect a different cell and hijack the other cell's protein-making equipment. The cell normally dies after infection as it is producing viral proteins instead of proteins useful to the organism. The infected 'host' cell normally bursts after virus infection.

All viruses infect other cells. Some viruses only attack a specific type of cell while some are more versatile. For instance the HIV virus often, but not always attacks T-cells, part of the immune system. Others known as bacteriophages attack only specific bacteria.

Other Harmful Organisms

There are other types of organism that infect people, such as prions (infectious proteins), fungi and parasites. The majority of infections the immune system must protect against, however, are those caused by bacteria and viruses.

In this entry, bacteria and viruses are referred to as 'pathogens'⁴. Each pathogen has antigens, which are specific features - usually a protein on its surface - that the immune system responds to.

Entering the Body

The best way to avoid infection by bacteria and viruses is to prevent them from originally entering your body. This is one of the important jobs of your skin, although you may not have thought that your skin is helping your immune system in such an efficient way! A cut, if it isn't kept clean, will go 'gunky' - the 'gunk' is very often due to an infection. People who loose large parts of their skin because of, say, burns, will very often get severe infections where the skin in broken.

Broken skin isn't the only route of entry for pathogens - many can be found in food. Most are, however, killed if the food is thoroughly cooked but others are on your hand, plate and knife and fork when you eat.

There are many defences in the gut against pathogens in food. Firstly, the entire gut is covered by a mucosal layer; secondly, your stomach contains strong acid that kills some of them. The bowel is also lined with harmless bacteria and it is difficult for the harmful bacteria to displace them to reproduce there.

If infected food is eaten, such as some that contains small amounts of harmful bacteria, then the body rapidly forces it out of the gut and out of the body - the person is sick and has diarrhoea. This is the effect of 'food poisoning'.

Another way of stopping harmful organisms from getting inside the body is to keep a layer of fluid flowing over a surface that pathogens might colonise. This forces pathogens out of the body before they can reproduce. In the lungs, goblet cells produce a layer of mucus and the ciliated cells force it to flow upwards, towards the person's mouth, where it is swallowed or coughed up. If the lungs or nose are infected then much more mucus than usual is produced, resulting in a cough or a runny nose.

If you were 'designing' a human being, you wouldn't want to have unnecessary holes through which pathogens could enter the body. Women do need to have an opening for sperm to enter when they are likely to conceive but they don't need this opening when conception is unlikely. For this reason, when a woman is not ovulating, there is a mucus plug over the opening of her womb; when she is ovulating, a different type of mucus, that doesn't act as a barrier to sperm, is produced.

The Complement System

The Complement System is a mechanism for activating the immune system. When activated, it attracts phagocytic cells and increases the blood supply to the damaged area.

The Complement System is made up of a number of proteins - about 10 - that are named 'C', for 'complement', followed by a number.

When the body is responding to the presence of a bacterial or fungal infection, one of the first things that happens is the protein C3 is cut to produce three new proteins - C3a, C3b and C3c - each of which has a important role in the defence against disease.

C3a

This activates Mast cells, which release chemicals that increase your chances of fighting disease. The chemicals cause blood vessels in the area around the infection to dilate, becoming more permeable, so it is easier for all the cells that fight disease to get to the site of infection. Some of the chemicals attract more neutrophils to the area; others attract Eosinophil cells, which are important in cases of infection by worms and other parasites. Some of the other chemicals break down the connective tissue, making it easier for the cells of the immune system to reach the infected area.

C3b

This is one of the most important proteins in the complement system and has a number of important roles:

• One of the main tasks of C3b is to stick to cells that it identifies as foreign, creating a target for the activated neutrophils and other phagocytic cells.

• It induces more splitting of C3.

• Another part of C3 splits C5 into two new proteins - C5a and C5b.

• C5a attracts phagocytes and activates them when they reach the site of infection.

• C5b joins up with C6, C7, C8 and C9 to puncture holes in bacteria cell walls - it doesn't harm our cell membranes because they are made of different chemicals.

What Activates the Complement System?

There are two main mechanisms to activate the complement proteins: the classical pathway, which was discovered first; and the alternative pathway, which is more common. In this sense a pathway is a series of reactions that lead to C3 being cleaved, which in turn leads to the complement system springing into action.

The alternative pathway occurs in response to yeast, fungus and bacteria cell walls in combination with some chemicals and C3b, which is always present in blood in small amounts. The classical pathway occurs when the antigen combines with one of two types of antibody and some of the complement proteins. The system is incredibly complex - for more detailed information about the exact chemical reactions that take place, see this site run by the University of Illinois.

The Next Line of Defence against Bacteria

The neutrophils are the cells in the body that kill most bacteria that live outside of your cells. Because they have a rather short life, they can only neutralise about 20 bacteria each. The bone marrow, therefore, produces neutrophils at a very high rate: approximately 150,000,000,000 a day.

Neutrophils fight bacteria that are in the tissue but outside of cells. In order to migrate to the sites of infection from your blood, they have to 'know' that attack from bacteria is taking place. A number of signalling chemicals can 'tell' neutrophils to move to the tissues. Some of these chemical signals are produced by bacteria themselves. In addition to this, the body has its own more complex system to alert itself to pending attack.

It is also important to stop neutrophils damaging the body's own cells by activating them, like priming a grenade, and 'telling' them what they may and what they may not 'eat'. This is done by antibodies and the complement system.

What Happens Once the Neutrophils Arrive?

A neutrophil will engulf the bacterium, ingesting it, and then digest it by injecting chemicals that will break it down. Most of those chemicals are enzymes that break down many of the chemicals that make up the bacteria. Neutrophils can kill only a few things - about 20 - before they start to die. Once a neutrophil has started to die, it will send out a signal of its imminent death by making characteristic signalling proteins, which it displays on its surface. These proteins attract another sort of cell known as a macrophage, which will arrive to 'eat' the neutrophils and the remnants of the bacterium contained in the neutrophil. Most of the chemicals are recycled. If a large number of neutrophils are dying in one place, the macrophages sometimes can't recycle them fast enough, which is how abscesses are formed. An abscess is a crust of neutrophils containing a clear fluid, which consists of bacteria and dead neutrophils. It is sealed so bacteria can't get out and more neutrophils can't get in.

Macrophages also play an important role in independently phagocytosing bacteria, as well as ingesting neutrophils, to reuse their proteins, that are near the end of their lives.

Some Bacteria can Escape

Some bacteria, such as the ones that cause tuberculosis and leprosy, manage to escape by inhibiting the immune response. They do this by releasing chemicals which interfere with the killing process, reducing the actions of the macrophage cells.

Hidden inside the macrophage, the bacterium cannot be attacked by the immune system. It travels with the macrophage through the blood or lymphatic systems, spreading the infection.

Once the Macrophage has Arrived

Assuming the bacteria didn't inhibit the action of the macrophage, the macrophage has done the first part of its job and the bacteria has been killed. It is likely that there will be many more of the same type of bacteria nearby - they never come alone - so the body starts to make preparations.

The macrophage takes the proteins from the bacteria it digested and breaks them down. It then displays them on its surface in special proteins known as Major Histocompatability Complexes Type II [MHC II] (Type I will be mentioned later in this entry). After a short period of time, one T-helper-cell will recognise the foreign protein in the MHC-II and start an immune response. The T-helper-cell's job is to recognise these MCH complexes and spot other infected cells.

What's a T-cell?

T-cells are matured in your thymus gland, which is in your chest - the 'T' stands for 'thymus'. There are two main types of T-cell, also called 'T-lymphocytes': T-helper-cells, which start an immune response; and T killer cells, which will be discussed later. All T-cells have a receptor that recognises one particular antigen. During their maturation, where they specialise, they are designed to recognise differently-shaped receptors. These receptors are manufactured at random and the ones that, by chance, would recognise a protein in a healthy cell of your body as an infection are destroyed.

The Function of T-helper-cells

T-helper-cells have two main roles - to help B-cells to start to produce antibodies and to release chemicals⁵ which stimulate the immune response.

If a T-cell meets a macrophage that has 'its antigen' in its MHC complex, it 'looks' for a B-cell that has a receptor for the same antigen as itself. B-cells are produced in bone, hence the 'B' and, when they are activated by a T-cell, they start dividing to produce more, similar B-cells. Some of these B-cells start reproducing quickly and mutating in an attempt to cause a random beneficial mutation that forms a B-cell more effective at combating the infection than the current B-cells. This takes place in your lymph glands, which become swollen when you're ill. Also in your lymph glands are cells that are known as 'interdigitating cells' - these have examples of the body's own proteins so that any new B-cells that dangerously recognise them as an infection can be quickly broken down.

The rest of the B-cells will multiply several times and eventually become plasma cells that produce antibodies.

What is the Purpose of Antibodies?

• Some antibodies block the parts of a virus that allow the virus to reenter the cell.

• Most of them bind with one end attached to the antigen and one end attached to something else. Many processes are started this way. The following can be activated in this way:

• The complement system
• Mast cells
• Neutrophils
• Eosionphils - these are similar to neutrophils but they act against much bigger antigens, such as worms, so they release the noxious substances onto the antigen rather than taking them into the cell itself.
• Macrophages - These can be activated by an antibody and a complement protein.



• Antibodies can also join antigens together to form an antigen 'mat', that cannot cause the body harm.

Can the Immune System also Defend against Viruses?

Antibodies are produced against viruses as described above - they attach to the part of the viruses that is used to get into cells. There is also another important mechanism of defence.

MHC I

Every cell in the body puts a sample of all the proteins that it makes on its surface using MHC I proteins. If a cell is infected, therefore, virus proteins are displayed and, if a T-helper-cell recognises these, they activate T-killer-cells that destroy the infected cell.

Some viruses try to avoid detection by stopping the cell from displaying proteins on its surface. 'Natural Killer' Cells, however, target cells that are not displaying sufficient amounts of MHC I for this reason.

Your Body can Remember Antigens

Once you have killed all the bacteria or all the virus, some of the B-cells and T-helper-cells remain and so allow the immune system to respond much more quickly to reinfection by the same bacteria or virus. When you are immunised against a disease, usually either a dead or inactivated form of the bacteria or virus is injected causing the immune system to respond as if the infection was real but without the risk of harmful effects to the person. If the person is infected later by the 'wild' form of the bacteria or virus, the immune system responds quickly enough for the person to, in most cases, not become ill.