Removal of an immune system signaling protein prevents the development of a lupus-like condition in mice, according to University and National Institutes of Health researchers.
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,” said 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 autoimmune disease treatments, but they 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, reported in the July 15 issue of the Journal of Experimental Medicine, a genetically modified line of mice lacking the SAP gene continued to be fit even after pristane exposure.
“The mice appear to be generally healthy,” Peng said. “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 affects the activity of surface molecules on immune system cells known as lymphocytes. Earlier research had shown that higher SAP levels were present in animals with autoimmune conditions.
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 said. “SAP may give us an important first insight into how these interactions occur.”
Peng and his colleagues plan to test if SAP is present at unusually high levels in human patients with lupus and to study how SAP removal or suppression affects other animal models of lupus.
“It’s going to be very interesting to see if this is a finding that can apply to lupus generally or if it is limited to a subset of lupus,” Peng said.
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, in which the immune system produces antibodies closely customized to attack inappropriate targets.