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New model can aid in understanding immune system diseases


New Model Can Aid In Understanding Immune System Diseases Researchers trying to understand diseases and develop new treatments can’t always depend on existing tools or organisms to make discoveries; sometimes they first must create models of the problems they want to study.

Such is the case with Epstein-Barr, a common virus that is often harmless but likely contributes to malignancies and autoimmnune disease in people with compromised immunity. A University of Iowa team has engineered a mouse that provides new insights into the virus.

The animal model has implications for advancing treatments for patients with AIDS or an organ transplant who get a certain type of cancer, and for people with immune system diseases such as lupus, arthritis and multiple sclerosis. The study results appear in the August issue of the journal Immunity.

The advance builds on previous UI studies done in cell culture and provides researchers with a model that allows them to see biological functions related to Epstein-Barr within the context of a whole organism, said Gail Bishop, Ph.D., Distinguished Professor of Microbiology and Internal Medicine in the UI Roy J. and Lucille A. Carver College of Medicine and a research career scientist with the Department of Veterans Affairs (VA) Iowa City Health Care System.

"Mice cannot be infected with Epstein-Barr because they do not have the receptor for this virus. What we have done is express in the mouse the most important transforming protein that is involved in the virus in humans," said Bishop, who also is associate director for basic science research at the Holden Comprehensive Cancer Center at the UI.

The Epstein-Barr virus, a member of the of herpes virus family, infects most people by adulthood, then remains latent (inactivated) after an initial and usually symptomless infection. People who get the virus in their teens or early 20s may get mononucleosis. But for people with AIDS or who are on immunosuppressive drugs to prevent rejection of a donated organ, there is a risk that the activated virus will produce a viral protein called latent membrane protein 1 (LMP1), which in turn can cause B cell lymphoma, or tumors, Bishop said.

The new mouse model will help researchers study how LMP1 impacts specific organs or tissues. Previous UI studies helped show that this viral protein mimics a normal cellular process in humans. In that process, a protein called CD40 signals B cells (white blood cells) to divide and make antibodies against infection, then terminates the signal when the need for the immune response is gone. LMP1 also triggers B cell activation, but in contrast to CD40, fails to stop it at the appropriate time.

"The viral protein is an amazing mimic of the normal protein but, in a way, the viral protein does its functions too well," Bishop said. "The viral protein causes abnormal survival and activation of these B cells."

Lymph nodes all over the bodies of these mice are enlarged by excess B cells. In addition, there is increased production by the B cells of antibodies against normal cellular components. These antibodies are called auto-antibodies.

"In humans, these auto-antibodies work against components of one’s own body and are seen in other autoimmune diseases such as lupus, arthritis, diabetes and multiple sclerosis," Bishop explained.

The researchers found that mice with LMP1 made excess auto-antibodies. This means that the mice could serve as a model for understanding how to prevent this overproduction in humans, with implications for not only Epstein-Barr Virus but also autoimmune diseases.

"Epidemiological studies show a correlative link between acute Epstein-Barr virus and autoimmune diseases, particularly lupus and arthritis," Bishop said. "We’re wondering, ’Where does this link come from?’ If the viral protein causes B cells to be hyperactive, this might increase the propensity of the small number of autoreactive B cells, which we all have, to become hyperactivated."

The team also found that mice with LMP1 have certain problems with how cells are organized in the lymph nodes and spleen.

"Normally, when a person gets an infection or vaccination, they develop a memory response. As a result, you have a particular organization of cells and tissue -- called germinal centers -- in your lymph nodes, spleen and lining of the intestine. When we looked at germinal centers in the mouse, we could see this tissue organization was disrupted," Bishop said.

By studying this dysfunction in mice, the team hopes to learn why the normal cellular protein CD40, but not the viral mimic LMP1, is able to signal to organize the cells and tissues.

"There are chemical messengers that cells normally use to tell each other where and when to go, so we will use the ’mimic’ mice to see if some of these chemical messenger are altered when LMP1 is present," Bishop said.

The team has other projects planned. The mice used in the study either had only a gene that coded for the normal protein or only a gene that coded for the viral protein. The team will breed mice that have one copy of each gene. These models may reveal whether the normal protein can suppress the abnormal protein, a function which, if it exists, could be useful in the development of therapeutics.

In addition to Bishop, major collaborators on the projects included the two lead authors Laura Stunz, Ph.D., UI associate research scientist, and Lisa Busch, a UI doctoral candidate in molecular biology who has since graduated.

Becky Soglin | EurekAlert!
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