Using molecular mapping of an immune memory cell ‘bio-antenna’ that EBV hijacks for its own ends, a Danish team has identified a tiny molecule that can foil the process and may be manipulated to block EBV’s role in immune system cancers.
The Epstein-Barr herpes virus (HHV-4) causes mononucleosis but is also associated with immune system cancers and autoimmune diseases. Infection with EBV means that the B cells, which are the primary memory cells of the immune system, are being hijacked.
Now researchers at the University of Copenhagen report they’ve found a way to regulate a special receptor or “bio-antenna” that plays a vital part when EBV infects us - and when this infection appears to be mutating into cancer of the immune system. (Their report was published online Aug 19 by The Journal of Biological Chemistry.)
When the virus has penetrated, researchers observe an excess of a special bio-antenna, a receptor known as EB12, suddenly sprouting from the surface of the B cells.
Exactly why this happens remains a mystery, because it can be hard to determine the part each molecule plays in a body involving millions of cells and transmitters.
But these EB12 receptors are a vital component of the way cells communicate with their surroundings - via hormones and other bio-molecules, for example.
Infected B Cells Sprout More Receptors, Multiply Faster. Why?
There are various theories regarding the EB12 bio-antenna receptors, says lead author Tau Benned-Jensen:
• "It is possible that the large numbers of EB12 receptors could actually be the B cells’ response to the virus and an attempt to combat the infection.
• “Another possibility is that the EB virus reprograms the cell for this explosive growth in the number of EB12 receptors.
• “What we know for certain is that more EB12 receptors assist the B cell infected by the EB virus to multiply more rapidly - thus spreading the infection faster."
The Epstein Barr Virus Can Cause Cancer
No fewer than 95% of us carry the Epstein Barr herpes virus. We often encounter it when very young and it is normally harmless, but if we are infected later in life EB virus may cause mononucleosis. And it seems to play a part in some forms of cancer, just as Human Papilloma Virus (HPV) affects the risk of cervical cancer.
But we have no drugs to combat the Epstein Barr virus, and no vaccines for it.
"Under normal circumstances our immune systems can keep the EB virus infection in a latent state, and a truce or stand-off may arise between the immune system and the virus," explains corresponding author Mette Rosenkilde, a professor of pharmacology at the University of Copenhagen.
"We cannot dispense with the infection and we carry it all life long, but to most of us it is harmless,” Dr. Rosenkilde explains. But “for people whose immune systems do not function due to disease or because they are suppressed by drugs in conjunction with organ transplants, it is a very different matter. Now the Epstein Barr virus is suddenly free to reproduce so uninhibitedly and dramatically that it may lead to cancer."
A First Step Toward Solving the EB12 Puzzle
While the Danish researchers do not yet know the exact role of the EB12 receptors, they do know that these receptors play a part when the cell visits the lymph glands (the immune system's Central Station).
So the team started by mapping the bio-antenna - molecule by molecule - and then made first-ever “blueprint” of a tiny molecule they thought could bind to the B cell EB12 receptor.
"When we know what receptors react to, it tells us more about the part they play," Dr. Rosenkilde explains, "and our tiny molecule, a ligand, blocks the EB12 receptor, preventing it from doing its job."
[Note: Ligands are signal triggering molecules or ions that bind to receptors, in this case apparently with an inhibiting rather than activating effect.]
"In time this block may be able to help transplant patients. If we can restrain EB virus reproduction when the immune system is being medically suppressed, we may well be able to avoid cancer," Benned-Jensen says.
"On the other hand the EB virus also appears to play a part in other immune diseases such as autoimmune disease, where the ability to adjust the immune system would be beneficial," says Dr. Rosenkilde.
Other Research Provides Additional Parts of the Puzzle
Shortly after these Danish researchers published the article on their ligand in The Journal of Biological Chemistry, the first articles appeared about natural substances in the body that activate the EB12 receptor and direct the B cell to specific areas in the lymph glands.
Accordingly, "Our molecule can inhibit the activation of the new substances, and the next step in our research will be experiments to identify even more biochemical dials to twiddle and to help us develop new drugs," Tau-Benned says.
Source: Adapted from University of Copenhagen news release, Aug 19, 2011