Infection 'Alarm' Yields Clues To Immune System Behavior

Collaborating with colleagues at the University of California, San Diego, the Johns Hopkins researchers have used their discoveries to develop a new computer model that could help produce medications for immune system-related ailments including septic shock, cancer, lupus and rheumatoid arthritis.
Their findings, which focused on how a large protein molecule called tumor necrosis factor, or TNF, triggers an immune response, were reported in the February issue of the Journal of Biological Chemistry.

"We were surprised by how sensitive cells were to small amounts and brief exposures to TNF," said Andre Levchenko, a Johns Hopkins assistant professor of biomedical engineering and senior author of the paper. "Our analysis may help drug companies solve problems with the regulation of immune response levels, and do it in a smart way."

In particular, Levchenko's team looked at the innate immune response, a localized reaction which normally stops an infection threat confined to a small part of the body, such as in the case of a pricked finger. (This is in contrast to a systemic response that triggers an immune reaction throughout the body, causing a fever. If the immune system responds too aggressively in such cases, the result may be a dangerous condition called septic shock.)
The innate immune response begins when white blood cells detect a bacterial intruder or toxin in the body. They produce TNF to carry a message about this health threat to neighboring blood vessel cells, asking them to join in the fight. To send this message, a TNF molecule latches onto the surface of a neighboring cell and accesses a biological information highway called the NF-kappaB pathway. Via a series of chemical reactions that act like signals traveling over a telephone wire, TNF's message moves along this pathway from the cell's surface to its nucleus.

At the end of this pathway, NF-kappaB molecules are released to carry the alarm into the nucleus, the cell's control center. Inside the nucleus, the NF-kappaB molecules switch on genes that produce infection-fighting proteins. These proteins launch several strategies to fight the microscopic invaders, such as sending more white blood cells to engulf the bacteria or toxins. The proteins also set off a response known as inflammation, characterized by redness, swelling and pain.
In their journal article, Levchenko and his colleagues reported several important new discoveries about this cellular signaling system. "You could think of the TNF molecule, which sounds the alarm, as a very weak radio transmitter. It moves very slowly as it carries its warning message to neighboring cells, so it is unable to send that message over long distances," Levchenko said. "However, we discovered that the cellular pathways that pick up this signal act like extremely sensitive radio receivers. They can pick up the alarm message from exposure to even a very small amount of TNF. This turns out to be a very smart strategy on the part of the cells."

He explained that a pricked finger usually generates a very localized fight against infection, involving only nearby cells. If TNF's signal was strong enough to set off an immune response involving the entire body, the result could be a high fever and septic shock. "We've developed a better understanding of why the fight against a local infection stays local," said Raymond Cheong, a graduate student in Levchenko's lab and lead author of the journal article.

The researchers also found that as TNF's warning message travels from the surface of a cell to its nucleus, it receives critical help from a molecule called Inhibitor of KappaB Kinase, or IKK. "IKK filters and interprets the warning message," said Cheong, who is an M.D.-Ph.D. candidate in the Johns Hopkins School of Medicine. "It carefully controls the level of the immune system's response."

That makes IKK a very promising target for new medications designed to boost or suppress the immune system, the researchers said. An overactive immune system, for example, can set off the excessive inflammation associated with rheumatoid arthritis and lupus. In addition, some cancers are more likely to grow where inflammation occurs. These ailments might be helped by a drug that curbs inflammation by reducing the sensitivity of IKK. Still other diseases that are characterized by a weak inflammatory response might be helped by a drug that makes IKK even more sensitive to infection messages.

The researchers believe their computer model of this cellular alarm system, which was refined through lab testing, should be a great help to medication makers. "Models like this are a wonderful tool for experimental drug testing," Levchenko said. Funding for the research was provided by the National Institutes of Health and the Medical Scientist Training Program at The Johns Hopkins University. Co-authors of the journal article included Adriel Bergmann, a graduate student in the Department of Biomedical Engineering at Johns Hopkins; and Shannon L. Werner, Joshua Regal and Alexander Hoffman, all of the Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego.