Autoimmune diseases, including rheumatoid arthritis, multiple sclerosis (MS) and asthma, exploit the chemical signals that are released when the body is wounded or under attack from disease. These signals, called chemokines, are sensed by receptors on white blood cells -­ the body’s natural defense system.

In healthy individuals, white blood cells are attracted by chemokines to the site of infection, where they can mop up viruses and other foreign agents. But for people suffering with autoimmune diseases, chemokines can also become involved in the generation and proliferation of the disease.

“It is appropriate to try to use our knowledge about the role of chemokines in disease to develop drugs that block the receptor and don’t allow the chemokine to bind,” says Dr. Graham.

Dr. Graham’s research team is currently trying to build up a picture of what the chemokine receptors on white blood cells look like so that they can develop "receptor antagonists" that may be able to block this reaction.

“We know these receptors are not straight proteins and, in fact, are called seven membrane-spanning receptors because the receptors, like a sea serpent, meander in and out of the cell membrane seven times,” continues Dr. Graham. “In trying to develop blockers, we really need to know precisely how the receptors twist and turn and fold at each point along its length. But doing this is difficult.”

The research group is focusing on one particular chemokine receptor called D6. For some as yet unknown reason, this receptor is easier to reproduce than other receptors.

The team makes tiny crystals of the receptor, then shines X-rays through them. The twists and turns in the receptor molecules cause the X-rays to bounce off in predictable ways, forming a diffraction pattern. The researchers then work backwards to find out the structure of the molecule.

“We have a long way to go before our goal is achieved, but we believe we can do it and that it will represent a very significant advance in our fight against a wide range of diseases,” says Dr. Graham.

Autoimmune diseases and inflammatory disorders

Chemokines can attract white blood cells to parts of the body where they are not needed, causing the white blood cells to attack healthy tissue and joints.

Examples of these diseases include rheumatoid arthritis, asthma and multiple sclerosis. About 80,000 people suffer from MS in the UK. It is the most common neurological disorder. Rheumatoid arthritis affects about 1 million people in the UK. About 75 per cent of autoimmune diseases occur in women, most frequently during childbearing years.

Cancer

In some cancers, the cancerous cells can inappropriately express receptors for chemokines ­- allowing these cells to travel around the body using the signals sent out for white blood cells. This process is known as metastasis and can cause tumors to spread through the body.

AIDS

It has been known for a number of years that HIV enters cells and ultimately causes AIDS by attaching itself to chemokine receptors on white blood cells. These receptors act as a gateway into the cell for the AIDS virus and are essential for infection by HIV.

This presentation was part of the From Genes and Cells to Healthcare conference organized by the Biotechnology and Biological Sciences Research Council (BBSRC) as part of the BA Festival of Science.

BBSRC channels public funds to university and institute scientists in the UK. Each year BBSRC spends about £230 million on research in the non-medical life sciences.

Related website:

Biotechnology and Biological Sciences Research Council (BBSRC)

[Contact: Dr. Gerry Graham, Andrew McLaughlin]

04-Sep-2001