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Release: Oct. 16, 2001

UI researchers receive grants to investigate immune system

IOWA CITY, Iowa -- University of Iowa microbiology researchers will use a five-year, $1,169,162 grant from the National Institute of Allergy and Infectious Diseases (NIAID) and a three-year, $260,000 grant from the American Heart Association (AHA) to advance their studies on an important component of the immune system. In addition to better understanding how the human immune system normally functions, their research has implications for organ transplantation, atherosclerosis and the treatment of a particular cancer associated with severely weakened immune systems.

Gail Bishop, Ph.D., UI College of Medicine Distinguished Professor of microbiology and internal medicine, and principal investigator on the NIAID grant, and her colleagues are investigating the actions of a protein called CD40, found in B-cell membranes. B cells are the white blood cells that make antibodies, which fight infection.

"CD40 is very important in the activation of B-lymphocytes," Bishop said. "CD40 delivers all kinds of signals to the cell. It tells the B cell to divide, to make antibodies, and to die off when the infection has been beaten and the need for the immune response is gone."

The CD40 protein consists of a portion outside the cell, which receives molecular messages, and a tail inside the cell that initiates the transmission of the signal to its final destination through a cascade of protein-protein interactions. Studies from Bishop's and other's labs found that a family of proteins, called TRAFs, interact with the CD40 tail and play an important role in the signaling cascade.

To investigate how TRAF proteins function, Bishop and her team have developed techniques to control how much and which type of TRAF, both normal and mutant, the B cell makes. The researchers can also control when the cell will start making the protein. This system allowed scientists to examine TRAF action at protein levels that mimicked the normal amounts of protein found in a B cell. Bruce Hostager, Ph.D., staff scientist in Bishop's lab and principal investigator on the AHA grant worked out many of these techniques, which have proved so important in studying CD40.

To investigate what happens when TRAF proteins and CD40 interact, the researchers first had to determine where in the cell the two proteins got together. Within a resting B cell the two proteins are in very different locations. However, within a few minutes of stimulation, both proteins end up in the same place, although the location was initially a mystery.

When the researchers used standard experiments to locate the proteins, they didn't find anything. Back-tracking, the researchers finally found the missing proteins in the insoluble parts of the cell membrane, in regions known as rafts.

These are patches of cell membrane that are rich in cholesterol and other fatty molecules. Because of their composition, the rafts attract important molecules that are key players in signaling pathways. These molecules like to reside in the fat-friendly environment of the raft domains.

"There are a lot of signaling components that 'hang out' in these patches. So the receptor and its friends that want to get together with signaling components in a cell, might want to move to these domains," Bishop explained.

Now that it is known where the TRAF proteins and CD40 get together, the UI team is investigating what happens to these molecules within the raft domain.

The UI researchers noticed that the amount of TRAF seemed to decline as the signaling process went on, suggesting that it is being degraded. The UI team is investigating how this process happens. The importance of the degradation became clear as Bishop and her team pursued a new line of research, which has implications for a cancer that is particular to B cells.

Epstein-Barr virus (EBV) is a herpes virus that infects B cells. This virus causes mononucleosis in young adults, and most people are infected with EBV by the time they are adults. In general, the latent infection is harmless and does not produce any symptoms. However, for individuals with a highly compromised immune system, such as people on immuno-suppressant drugs after an organ transplant or individuals in the later stages of HIV infection, EBV can reactivate and it can turn a B cell into a B cell lymphoma. EBV associated lymphoma is now a major clinical complication of transplant biology.

Epstein-Barr virus makes a protein called LMP1 (latent membrane protein 1) that is absolutely required to transform a B cell into a B cell lymphoma. It was recently discovered that LMP1 interacts with a TRAF protein. This similarity of a cancer-causing protein with the CD40 protein excited Bishop and she and the colleagues started to investigate the EBV protein.

The UI researchers found that the EBV protein mimics CD40 strikingly in the B cell. It does all the things that CD40 does: it preserves viability, and it activates the cell to divide and make antibodies. However, the EBV protein causes much more powerful signals in B cells than does CD40.

"We found that in all the things that these two proteins can do to a B cell, the LMP1 protein does it faster, longer and stronger," said Bishop who also serves as director of the Cellular Activation in Cancer Program of the Holden Comprehensive Cancer Center at the UI.

Knowing that TRAFs are normally gradually degraded over the course of CD40 signaling events, the researchers noticed that when the EBV protein was controlling the signal, the amount of TRAF did not decline during the signaling process. Activation turns the cell on, and the TRAFs subsequent removal seems to act like a dimmer switch, slowly turning off the signal. However, the EBV protein turns the cell on, but somehow the dimmer mechanism does not work and the signal stays on.

In parallel with their on-going studies on CD40, Bishop and her team in collaboration with George J. Weiner, M.D., director of the Holden Comprehensive Cancer Center and C.E. Block Professor of Cancer Research and Internal Medicine at the UI, have started to investigate LMP1 signaling in human B lymphomas.

"It's exciting to bring the knowledge we gain about a normal cellular protein, CD40, to bear on what goes wrong in a signaling pathway in cancer," Bishop said.

In addition to Bishop and Hostager, other UI researchers involved in these studies include Lisa Busch, Ph.D., Kevin Brown, Ph.D., and Mekhine Baccam, Ph.D., all of whom recently earned their doctoral degrees in Bishop's lab; Sokol Haxhinasto and Carissa Moore, graduate students; Ping Xie, Ph.D., and So-youn Woo, Ph.D., postdoctoral fellows; Laura Stunz, Ph.D., staff scientist, and Luis Ramirez, research technician.

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