Lack Of Immune System Protein Prevents Lupus-like Condition In Mice

If additional studies in other animal models and humans confirm that SLAM-associated protein (SAP) is a primary contributor to lupus, it may be an ideal target for the development of new drug treatments, scientists said.

"What's perhaps most exciting is that normal immune system functions were still largely intact in the experimental mice that lacked SAP," says Stanford Peng, M.D., Ph.D., assistant professor of medicine in rheumatology and of pathology and immunology and lead investigator for the study. "Other immune system proteins are potential targets for new autoimmune disease treatments, but they all affect large portions of the immune system, making weakened immune function a potential side effect of any new drug. Targeting SAP for treatment may avoid that risk."

Scientists have used several animal models to study the immunological underpinnings of human lupus, a condition that afflicts approximately 1.5 million Americans with arthritis, prolonged fatigue, skin rashes, kidney damage, anemia and breathing pain.

In one of these models, exposing mice to a hydrocarbon oil known as pristane causes mice to develop a condition with many similarities to human lupus, including kidney disease and arthritis. But in the new study, available in the July 15 issue of the Journal of Experimental Medicine, a genetically modified line of mice continued to be fit even after pristane exposure. Created by National Institutes of Health researcher and coauthor Pamela L. Schwartzberg, the mice lack the SAP gene.

"The mice appear to be generally healthy," Peng says. "They have none of the lupus-like symptoms of the control group, and their immune systems generally respond to vaccinations like those of normal mice."

SAP, also known to scientists as SH2D1A, affects the activity of a number of surface molecules on immune system cells known as lymphocytes. Earlier research had shown that higher levels of SAP were present in animals with autoimmune conditions than in normal animals.

Instead of disabling whole groups of immune system cells, SAP's removal seems to disrupt communication between two different types of immune cells, T and B cells. Scientists have long known that T cells help B cells produce antibodies meticulously customized to destroy the last scattered remnants of a persistent invader. But they've had a hard time determining the details of how those interactions take place.

"We know a lot of molecules that are important to the activation of T and B cells, but we have never understood what was important for their interaction," Peng says. "SAP may give us an important first insight into how these interactions occur."

Peng and his colleagues plan to study how SAP removal or suppression affects other animal models of lupus, and to test if SAP is present at unusually high levels in human patients with lupus.

"Each of the animal models of lupus has slightly different clinical aspects to it, probably because they represent a slightly different facet of the human disease. It's therefore going to be very interesting to test if this is a finding that can apply to lupus generally or if it is limited to a subset of lupus," Peng says.

Based on how thoroughly SAP's removal appears to disrupt T and B cell interactions, which are essential to producing the pathogenic antibodies seen in lupus, Peng suspects the finding will be generally relevant.

Peng also wants to explore potential connections between SAP and other autoimmune diseases including allergies and myasthenia gravis.

"Like lupus, these other autoimmune conditions involve the immune system producing antibodies that are closely customized to attack targets they shouldn't be attacking," he explains. "So SAP may be a contributor to these conditions as well."

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Hron JD, Caplan L, Gerth AJ, Schwartzberg PL, Peng SL. SH2D1A regulates T-dependent Humoral Autoimmunity. Journal of Experimental Medicine, July 15, 2004.

Funding from the Lupus Research Institute, the Arthritis Foundation, the National Institutes of Health, the Siteman Cancer Center, and the Diabetes Research and Training Center and the Digestive Diseases Research Core Center of the Washington University School of Medicine supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.