White blood cells and warning bells
Reproduced from Issue 108 of Arthritis Today
In the second of a series of articles aimed at simplifying science, Professor Brian Henderson of University College, London, explains the role of white blood cells (leukocytes) in arthritis.
If you look at the back of your hand you can see the veins that carry your blood. Blood is red because most of the cells contain the red pigment, haemoglobin. What you can't see in blood are the white blood cells (or to give them their technical name – leukocytes [Leukos is the Greek for white]). These leukocytes have the job of defending you from the huge numbers of bugs (bacteria, viruses and so on) that live, hidden, in the environment. The danger of these bugs has become apparent in recent years with regular reports of 'flesh-eating' bugs, meningitis and dangerous strains of E. coli appearing in our papers and on TV.
There are many different types of white blood cells. Some of them have the job of eating and killing bacteria. Cells which eat bacteria are called phagocytes, and the two major bug-eaters in our blood are the polymorphs (so-called because of the shape their DNA takes) and the macrophages (Greek for big (macro)-eater (phage)). These cells can recognise bacteria, eat them and then, when they are inside the cell, kill them. But to do their job properly they require other leukocytes to help them. The most important of these cells are the lymphocytes.
There are two main types of lymphocyte. The B lymphocytes produce a very important molecule called the antibody molecule. Antibodies are what we produce when we are vaccinated. The antibody molecule can recognise foreign molecules (e.g. bacteria or viruses) and can bind to them. If the foreign molecule is a bacterium then this binding can help the phagocytes recognise and eat it.
The other type of lymphocyte is called the T lymphocyte. This also produces a molecule like the antibody, which is called the T cell receptor (TCR) because it exists on the surface of the T lymphocyte. These T lymphocytes can help B lymphocytes make antibody. They can also help macrophages kill the bacteria that they have eaten. All the interactions between these various cells are controlled by signals that were described in the first article in this series – the cytokines.
To recap, our white blood cells function to defend us against parasites, be they viruses, bacteria or the larger organisms that cause diseases such as malaria or river blindness. The phagocytes represent the older form of our defence mechanisms. The B and T lymphocytes are more recently-developed defence mechanisms and have a special system for producing the antibody molecule and the T cell receptor (TCR) that are capable of recognising molecules (the technical term for the molecules recognised is – antigen).
It has been estimated that B lymphocytes can produce 100,000,000,000,000,000,000 (100 British trillion) different antibody molecules. This is, literally, an astronomical figure and carries with it an enormous danger. The B and T lymphocytes produce molecules that recognise foreign antigens. However, in producing so many different forms of antibody or TCR the danger is that some of these lymphocyte molecules will recognise and attack non-foreign antigens – that is – us. If lymphocytes produce antibodies or TCRs which recognise antigens in our own tissues, then these tissues will be attacked by the phagocytes and will suffer damage. When this happens then we say that the patient is suffering from an autoimmune (Auto – self) disease.
It is precisely this scenario that we believe occurs in the autoimmune disease, rheumatoid arthritis. For some reason, which is yet to be discovered, those individuals who suffer from rheumatoid arthritis have immune systems that appear to recognise as foreign some constituents in their joints. B and T lymphocytes enter into the joint and in turn call in the phagocytes – polymorphs and macrophages – to the party.
The entry of all these white blood cells into the joint produces a large number of cytokines which cause the joint to be painful, result in the joint becoming swollen and slowly cause the damage to the joint which leads it to become disfigured and unable to work properly. The joint damage is caused by the release of special proteins (called proteinases) which destroy the large molecules of which the articular cartilage and bone are composed. How this happens will be told in a later article.
This article started off talking about white blood cells and infection. Does infection have anything at all to do with rheumatoid arthritis? The truthful answer to this question is – we don't know. However, it is recognised that when we become infected we make large amounts of antibody to one particular group of proteins known as stress proteins. These are very important molecules, present in all living creatures that are increased in number in any cell that is stressed. Now when bacteria enter the human body they are in a foreign environment and are therefore stressed. Therefore they make large amounts of these stress proteins. The ability to respond to stress is vital for all living creatures and because of this the stress proteins of bacteria are very similar to our own stress proteins.
It has therefore been proposed that the antibodies (and the activated T lymphocytes) that we produce in response to bacterial stress proteins could also recognise our own stress proteins and, as a consequence, cause autoimmune disease. In addition to possibly having a role in rheumatoid arthritis, it has been suggested in recent years that our antibody responses to stress proteins can also cause heart disease.
Knowing that leukocytes are the driving force of rheumatoid arthritis how can we use this information to treat disease? One obvious way is to inactivate these cells, and in the first article in this series the role of neutralising the key cytokine – tumour necrosis factor (TNF) a – was discussed. Preventing leukocytes getting into the joint is an obvious approach which is being examined by the drug industry and which will be discussed in a later article. Another method is to try and remove or kill the key leukocytes using antibodies which recognise them. All these approaches have limitations but could, if properly tailored, be new therapies for rheumatoid arthritis.
