SECRETS OF THE IMMUNE SYSTEM
Alan G Baxter

Comparative Genomics Centre,
Molecular Sciences Bldg 21, James Cook University,
Townsville, 4811, Queensland, Australia
Telephone: 61-7-4781 6265 Fax:  61-7-4781 6078








Broadcast 11/5/2008

Robyn Williams: As we approach the Olympic Games it's natural we should think of Australia as world beaters at swimming, maybe rowing, and a couple of other sports, too. But did you know that our immunologists are every bit as golden as the swimmers, with the added bonus that they keep you alive as well.

The list of immunologists to go with swimmers like Fraser, Gould, Konrads, Thorpe, Trickett, Hackett and others, is every bit as magnificent, topped by Burnet and Florey, with Nossal, Corey, Miller, Metcalf, Doherty, Adams and plenty more down the line.

And we've just had a day to toast their achievement, as Professor Alan Baxter in Townsville is here to tell you. Dr Baxter is President of the Australasian Society for Immunology.

Alan Baxter: This talk is to mark World Day of Immunology, which is held on April 29th each year. All over the world, including Australia, people attended public talks, demonstrations and laboratory tours to learn a little about their immune system and how it works.

The immune system is a collection of organs, cells and cell hormones that protect the body from infections and cancer. Because protection from infection is so critical to our survival, almost every aspect of our biology, every surface, every secretion and every cell, has evolved to help.

For example, although saliva is 98% water, it contains the antibacterial agents lactoferrin, which binds the iron that bacteria need to grow, and lactoperoxidase, which kills bacteria by producing oxygen radicals.

Tears contain lysozyme, an enzyme that destroys cell walls of many bacteria, and which was discovered by Australian Nobel Prize Winner, Howard Florey.

In the disease Sjogrens Syndrome, the tissues of tear and salivary glands are destroyed. As a consequence, these women can develop corneal infections and tooth decay.

The windpipe and the air passages of the lungs are lined by cells that produce mucus and cilia, which are tiny hair-like projections that beat in time, like seaweed in the waves. Cilia sweep dust, bacteria and the mucus back up the windpipe to be swallowed and dumped into the stomach.

People who smoke cigarettes damage these delicate cilia, and are prone to lung infections, especially bronchitis.

The stomach contains acid to aid the digestion of proteins, but with a pH of 2, it is much more acid than is necessary just for that. The stomach acid sterilises much of what is swallowed, including the dust and bacteria coughed up from the lungs.

But I don't want to give the impression that the body is sterile. Like the world around us that is inhabited by micro-organisms, we are hosts to bacteria, viruses, fungi and parasites. 10% of our dried body weight is bacterial. Large proportions of our genome are, or have evolved from, viral sequences.

The mitochondria that live inside each of our cells, and produce the cellular energy we need to live, appear to be very well adapted bacteria that have lost the ability to live independently.

So the immune system has not evolved to deal with organisms unless they cause actual harm. It responds to infection, not colonisation.

Many of the micro-organisms that live in us, and on us, actually help to protect us from harmful infection. For example, our large intestines are filled with harmless E. coli bacteria that compete with harmful bacteria for nutrients. They therefore provide resistance against the E. coli that cause diarrhoea, intestinal bleeding, and kidney failure. Traveller's diarrhoea results from turf wars between your own intestinal flora, and those of the people preparing your food.

Our skin, which is made of a waxy layer of dead skin cells, is covered with a lawn of Staphylococcus epidermidus bacteria. These bacteria acidify the surface, making it difficult for other bacteria to grow there. Exposure to antibacterial soaps, and harsh disinfectants, kills these helpful bacteria, weakening our skin's defence against infection.

From the point of view of a scientist, some of the most interesting bits of the immune system are the white blood cells. Although these cells can be found in the blood, they spend much of their time in the lymphoid organs: the lymph nodes, and the spleen. The lymph nodes are the glands a doctor feels for in your neck, under your arms and in your groin, when you have the flu. The spleen is a fleshy organ, about the size of your hand, tucked in behind your stomach and below your heart and diaphragm.
It also enlarges in infections, alarmingly so in glandular fever, when the spleen commonly ruptures, if contact sports are played before complete recovery.

There are three major populations of white blood cells: the macrophages, the T cells, and the B cells. Macrophages are big eaters, which is what their name means. They patrol through the tissues, as well as through the body's internal surfaces, and engulf and digest bacteria found within the body. T cells and B cells look quite similar to each other, and it was Australian Jacques Miller who realised that these cells differed.

B cells make antibodies, which are the proteins that circulate in the blood and tissue fluids and neutralise foreign cells, such as bacteria, by binding to their surfaces. Once antibodies have bound to bacteria, it is much easier for macrophages to dispose of them. As a generalisation, B cells need two things to happen for them to be able to make antibodies. First, they must bind to and recognise the targets for which they are specific. In order to do this, they express on their cell surfaces, examples of the antibody they can make. The second requirement for B cells to make antibodies is that they need to get permission from T cells.

There are two kinds of T cells that we distinguish by the molecules on their surfaces. The ones that work together with B cells, bear a molecule called CD4. Because CD4 T cells help B cells to make antibody we sometimes call them 'helper' T cells. In order for B cells and CD4 T cells to work together, they must get together. They do this in the lymphoid organs: the lymph nodes and the spleen.

Like B cells, T cells have molecules on their surfaces that specifically recognise proteins that do not belong. Whereas B cells use bound antibody molecules for this purpose, T cells use a special receptor we call the T cell receptor. Whereas B cells can recognise the native surfaces of foreign invaders, T cells have tunnel vision, and can only see small fragments of protein sequence. B cells and macrophages assist T cells in recognising foreign sequences by holding the protein fragments down for inspection.

In response to bacterial infection, B cells bearing antibodies that can bind the bacteria engulf the bacteria, breaking their proteins into fragments, for inspection by T cells. The CD4 T cells that can recognise the fragments become activated, start multiplying and activate the B cells holding the fragment. The activated B cells then start multiplying as well as making antibodies.

As the responding B and T cells keep multiplying, their numbers become larger and larger, forming a formidable army of responding cells, which only starts to shrink again once the invading bacteria have been eliminated.

The end result is that the infection is routed, and the only signs that it was ever there are the slight increases in the numbers of specific T cells and B cells and the presence of anti-bacterial antibody circulating in the blood.

The other type of T cells bear a molecule called CD8 and play an important role in destroying viruses. There are key differences between viruses and bacteria, which require a different approach to their elimination.

Viruses are generally much smaller than bacteria and while most bacteria are free living, viruses need to enter the host's cells and take over the cells' replication machinery in order to reproduce themselves.

Once a virus has entered one of our cells, the only way to kill it is to kill the cell as well. The CD8 T cells have this responsibility and as a consequence, we sometimes call them killer T cells.

Like the CD4 T cells, they recognise fragments of foreign proteins being held for inspection by another cell. But in this case, the cell presenting the fragment is the virally infected tissue cell. Once activated by an infected cell, the CD8 T cell releases toxic granules and starts multiplying. The CD8 T cells, expanding in response to a viral infection, like the flu, can multiply up to 100,000 times their original numbers.

The tissue damage they cause can sometimes be a significant problem. A few days into a cold, your snot turns green or yellow, because it contains the corpses of the infected cells, killed by your anti-viral CD8 T cell response.

The liver damage associated with viral hepatitis is not a consequence of the actions of the virus, but the result of the scorched earth policy of the CD8 T cells.

However at the end of the day, if the virus can be eliminated, the numbers of CD8 T cells decline again, and often the only sign there was ever an infection is a slight increase in the number of virus specific CD8 T cells.

As a generalisation, the CD8 T cells work best if they are helped by CD4 T cells as well. In fact, in most immune responses, all the cell types work together. For example, your immune defences against flu include antibodies to neutralise the virus before it enters cells, and CD8 T cells to mop up after any successful viral sorties.

So what goes wrong in AIDS?

HIV is a virus that invades the CD4 T cells, ruining them, and setting them up as targets to be killed by the CD8 T cells. The CD8 T cells can kill up to 10-million infected CD4 T cells per day in someone with HIV.

The progression of the disease can be monitored by measuring the declining numbers of CD4 T cells. Without CD4 T cells, your immune system is helpless, literally. Many of your B cells fail to make antibodies, or fail to make effective antibodies, without permission from CD4 T cells. Similarly, the expansion of CD8 T cells, in response to a viral infection, is extremely limited in the absence of these cells.

As a consequence, people with low numbers of CD4 T cells become infected by microbes that would normally be harmless. People who are infected with HIV and do not respond to anti-viral treatment, or do not receive it, usually die of infection or cancer, resulting from the failure of their immune system.

Another problem that can affect the immune system is autoimmunity. Autoimmune diseases are those in which the immune system attacks the body's own tissues. Examples are childhood diabetes, multiple sclerosis, and thyroiditis.

In each case, some T cells and B cells, that recognise components of our cells or tissues, become activated. They proliferate, produce antibodies, and can kill our tissue cells as if they were virally infected.

We don't understand all we would like about what causes autoimmune diseases, but as a generalisation, drugs that suppress the immune system can help control them.

One of the strange paradoxes of HIV infection is that it can induce some types of autoimmunity. Patients occasionally develop B cells and antibodies against their blood platelets, causing clotting problems, or T cells against the tissues of their eyes, causing blindness.

A clue to what is happening here comes from a side effect of some of the newer, very powerful anti-HIV drug treatments. As these drugs take effect, the numbers of CD4 T cells can spring back from very low levels to repopulate the body with near normal numbers. To a large extent, this is achieved by driving the proliferation of the few remaining CD4 T cells.

A consequence of this is that these cells become activated, and if they happen to be reactive to the body's tissues, they can cause disease. Sometimes the outcome is autoimmune thyroiditis, resulting in a loss of thyroid hormones. This suggests that the mild autoimmune diseases sometimes seen in AIDS patients who do not receive the powerful anti-HIV drug treatments, are also caused by the CD4 T cells' attempt to repopulate the body. But in this case, because of ongoing activity of the virus, this proliferative drive is futile, and only delays the collapse of immune function.

Robyn Williams: Alan Baxter on what you have to do to stay alive. I hope you've got your Ts and your Bs on effective standby for this winter's flu. Professor Alan Baxter is President of the Australasian Society for Immunology and Professor of Biochemistry at James Cook University in Townsville, here to mark World Immunology Day, just passed.

Next week Stephen Schneider takes on Don Aitkin's two talks about Global Warming.

I'm Robyn Williams.


'Secrets of the immune system' is © Alan G Baxter 2000


LINKS:

Autoimmunity Research Group, Centenary Institute of Cancer Medicine and Cell Biology, Key words: Autoimmune diabetes, Type 1 diabetes mellitus, childhood diabetes, lupus, systemic lupus erythematosus, hemolytic anaemia, hemolytic anemia, Coombs' test, antinuclear antibodies, renal failure, glomerulonephritis, gastritis, type A gastritis, pernicious anemia, immunology, popular science, biology.