For some time, doctors have suspected that the Epstein-Barr virus (EBV) - the culprit behind infectious mononucleosis - may be related to the development of systemic lupus erythematosus (lupus) in certain people. A new study partly supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) helps confirm the connection. It also begins to explain how the virus may get the disease started and, ultimately, how some cases of lupus might be prevented.

Using serial blood samples from U.S military recruits as well as samples from the Oklahoma Clinical Immunology Laboratory, NIAMS-supported researchers studied changes in the blood of people who later developed lupus. They were able to identify when people with lupus began to make the self-destructive antibodies that target and damage tissues, including the joints, skin, blood and blood vessels, kidney, lungs and brain.

For many, the antibodies were first produced in response to EBV infection (as evidenced by antibodies to virus). In genetically predisposed people, antibodies to a portion of the EBV protein cross-reacted with a piece of a protein in the body called Ro. In other words, the immune system, revved up to fight the EBV virus, mistook part of the body for part of the virus and produced antibodies (autoantibodies) against the body's own protein. Later studies showed that the same phenomenon occurred in rabbits injected with this same portion of the EBV protein.

This phenomenon, called molecular mimicry, has been implicated in a handful of diseases, most notably rheumatic fever. In rheumatic fever, genetically susceptible people produce antibodies to proteins in the heart valves in response to infection with strep bacteria. But this is the first time molecular mimicry has been proven to play a role in lupus.

Although EBV infection has been implicated as a cause of lupus, proving an association has been difficult for a number of reasons, says study coauthor Judith James, M.D., Ph.D., of the Oklahoma Medical Research Foundation in Oklahoma City. One reason is that most people are infected with EBV at some point and relatively few develop lupus. In fact, for most people EBV infection causes only mild (if any) symptoms. Also, because doctors couldn't predict which members of the population would eventually develop lupus, analyzing blood samples prior to the disease's development was not practical or even possible. The Department of Defense Repository - which banks blood samples from military personnel at the time they enlist and periodically thereafter - provided the de-identified samples needed to perform those analyses. The researchers identified military personnel who developed lupus and then were able to look at their blood samples as far back as over a decade before symptoms started. This allowed researchers to look at the first changes in the blood that led to the disease.

Serum samples from the Oklahoma Clinical Immunology Laboratory, which includes banked blood from family members of patients, were also analyzed.

Although the study does help confirm that EBV can trigger lupus in susceptible people, it doesn't show whether lupus always develops the first time a person is infected with the virus, says Dr. James. "One of things that is very interesting about EBV is that it is a latent virus," she says. "Once you're exposed to the virus, it infects your B cells and is present in your bloodstream at some level throughout your entire life. Different people have different levels at different times. It may be that even if you are genetically predisposed, you may survive and live just fine until the environmental exposure is too high or it reactivates or for some reason you make this inappropriate immune response."

Dr. James says the study does more than provide new insight into how lupus begins. It also has implications for treating or even preventing the disease though vaccinations against EBV or drugs called tolleragens that could retrain the immune system not to recognize the mistakenly targeted proteins as foreign. "If we could identify susceptible people at the right point," she says, "[perhaps] we could stop this response from happening."

In addition to NIAMS, NIH institutes and centers helping to support this research were the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Research Resources, the Office for Research on Women's Health and the National Center on Minority Health and Health Disparities. The Presbyterian Health Foundation and U.S. Department of Veterans' Affairs also helped fund this research. The institutions involved in the study included the Oklahoma Medical Research Foundation, the Oklahoma University Health Sciences Center, the U.S. Department of Veterans Affairs Medical Center in Oklahoma City, Walter Reed Army Medical Center, and NIAMS.

The mission of NIAMS, a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

# # #

McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nature Medicine 2005;11(1):85-89.