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Author Topic: The Genetic Basis of Lupus  (Read 5778 times)
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« on: January 06, 2007, 09:58:19 pm »

The Genetic Basis of Lupus


The evidence that lupus is a genetic disease is quite clear. Lupus runs in families. If you have lupus, there's a five percent chance that one of your siblings will get the disease.

Lupus is an illness in which the immune system appears to have gotten confused. Instead of attacking viruses, bacteria, or cancer cells -which is what it's there to do- the immune system attacks the person's own body.

The evidence that lupus is a genetic disease is quite clear. Lupus runs in families. If you have lupus there's a five percent chance that one of your siblings will get the disease.

If you are a non-identical twin, the chances are about the same as for a sister, suggesting that nothing major happens in the womb to cause lupus. But if you are an identical twin -and your twin has lupus- the chances go up to 57% that you will develop the disease. Thus, there is strong evidence for a genetic basis, but it is clearly not a simple genetic basis.

If just one gene you could inherit always caused lupus, at least one out of four siblings should get lupus, considering the classic laws of genetics. Some people who are related to lupus patients have various lupus-like symptoms, suggesting that they have acquired "incomplete lupus" without developing the full blown disease.

So how do we explain that? And, since identical twins are genetically identical, why does lupus affect only 57% of identical twins? We're just beginning to understand that there are several possible explanations.

Multiple Genes Involved
The first important concept is that more than one gene may be involved. One fourth of your siblings should inherit any one gene, but if three, four, or more different genes need to be inherited together, this doesn't explain why both identical twins don't get the disease, since they inherit the same genes.

A concept that could explain why some identical twins of lupus patients are spared is called gene penetrance. This means that you can have a gene -and that gene may cause you to be susceptible to a disease- but the illness still doesn't show up. This is possible because something in the environment is needed to get the disease started. This environment can be outside your body -or the environment inside your body which is greatly influenced by infections or toxins, or even your other genes. The idea that a certain gene could be there- but not expressing itself completely -is called "incomplete "penetance.'''

A third concept, developed in recent years, is that there are cases where genes actually change or rearrange themselves in the body after the first cell divides at the moment of creation. So even identical twins can end up with somewhat different genes that develop later, after they have separated from each other in the womb, or after birth. This can be true for certain genes that have to do with the immune system.

The Role of Genes
What do we know about lupus that helps us to understand the roles of genes? First, there is the predominance of women to men, who get the disease. It seems likely that this has to do with a direct effect of hormones on the immune system. Female hormones may help create the environment that allows a lupus gene to penetrate.

Much research is being done to identify the genes that lupus patients share. The ones that are best understood are a series of genes which regulate how the immune system works, and where and when it might attack.

These genes are part of the network that is involved in tissue typing. They allow the immune system to recognize and attack foreign invasions from viruses, bacteria, or cancer cells, and to distinguish them from things that should not be attacked such as parts of the body or tissue-typed organ transplants.

If you were looking for a defective gene that causes lupus, MHC genes would be good candidates since the immune system in lupus gets confused into attacking a person's own body. And, in fact, MHC genes are shared by many lupus patients.

How Genes Work
How do these genes work? They make proteins that act very much like the Lord Chamberlain to a very paranoid Queen. Imagine a world in your bloodstream that is rather like medieval times with lots of small castles, each inhabited by a different Queen, each Queen waited on by a special court made up of one Lord Chamberlain and a lot of little soldiers.

If an infection enters the bloodstream an invading particle will be picked up by a special Lord Chamberlain, who is genetically programmed to recognize it. He takes the particle back to his own castle and finally presents it to the Queen as if it were the ambassador from a foreign country. The Queen takes one look at the particle and shouts, "Off with ist head!" -and all sorts of things start to happen.

First, immune-fighting cells get made. Then little proteins called antibodies get made. These are like little soldiers who specifically know how to recognize that original invading particle. So they leave the cells and run around the blood stream attacking anything that looks to them like the particle.

If they get confused and think your kidney or joints look like an invading particle, then you might develop lupus. But the antibodies would never have started attacking if the Queen hadn't started shouting. And the Queen would have kept quiet if the Lord Chamberlain had brought the particle into her castle.

The Lord Chamberlain (who is an MHC molecule) may be shared by many lupus patients and may be one of the primary genes that put people at risk. The Queen (who is called the T Cell Receptor) and the antibodies are examples of immune genes that can rearrange themselves after the beginning of life, so they may or may not be shared exactly in families, even by identical twins. This could explain why an identical twin of a lupus patient might have more risk of developing lupus than another sister, but not a 100% risk.

Self Attacking Genes
But why do lupus patients carry these genes in the first place than can start an attack on their own bodies -and what prevents other people from doing the same thing? In order to have a diverse ability to recognize and protect the body from diverse infections over a lifetime, everybody has some genes capable of making proteins that attack their own organs.

However, immune cells go through a complex educational process early in life in the thymus gland, where they are taught to recognize the difference between "us" and "them"- and what sorts of invaders it is appropriate to attack. Those that misbehave and threaten to attack parts of their own bodies are usually simply killed off by a process called apoptosis. But the well-behaved immune cells "graduate" from the thymus, and are allowed to enter the bloodstream.

A gene which regulates the system that eliminates self-attacking cells in the thymus gland is defective in some mice with a lupus-like illness. The jury still out on whether this is the fact in human lupus -but many researchers are now considering the possibility.

I cannot go into all the other genes that seem to put people at increased risk for lupus. But one important set of genes gives rise to special inflammatory proteins called complement proteins. These proteins act something like the artillery used by the antibody soldiers when they attack, and defects in some of the complement genes have been described in lupus and lupus-like illnesses.

Continued Research Needed
In summary, lupus is a complicated disease with a complicated genetic basis. It involves several genes we know of, and probably more not yet identified, that are important to regulating appropriate immune activity.

There are two reasons why continued research into the causes and genetic basis of lupus is very important.

First, and foremost, to improve the care of lupus patients. Although treatments today are better than 20 years ago, and we encourage lupus patients to have optimism for a fairly normal life, people still die from lupus, or from side effects of the medications. And others become very ill and suffer major organ damage. Patient care could be better if we knew more.

Second, what we learn by studying lupus has profound implications for better understanding and treatment for many other diseases. This point should not be forgotten when writing to congress- people, or fundraising for the Lupus Foundation.

Lupus research provide a large picture window into the mysteries of the immune system, and will very likely contribute to The understanding and treatment of AIDS, heart disease, cancer, diabetes, and many other diseases. This includes the one disease that costs more than any other- and affects everyone on earth the process of aging itself.

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