RAGE, first identified a decade ago at P&S, is an aptly named molecule that plays a role in numerous diseases, including diabetes, atherosclerosis, and Alzheimer's. RAGE, or the receptor for advanced glycation end-products, does not instigate the conditions, but escalates the immune and inflammatory response against the body's own cells and tissues and worsens the disease symptoms.
Now P&S researchers have discovered another disorder, multiple sclerosis, can be added to the growing list of diseases exacerbated by RAGE. Dr. Shi Du Yan, associate professor of clinical pathology, and colleagues also have found that blocking RAGE activity on the immune cells can prevent most symptoms in mice with an induced multiple sclerosis-like disease. The research is reported in the March issue of Nature Medicine.
Multiple sclerosis is an autoimmune disease of the central nervous system. So far, few effective treatments exist to slow progression of the disease's lesions on the spinal cord, which result from an immune attack on a substance called myelin that covers nerves and helps them conduct signals. Patients, as a result, experience a failure of nerve transmission and can become significantly debilitated over time. Though RAGE had not been linked to multiple sclerosis, Dr. Yan says she and her colleagues thought RAGE might be involved in the disease because RAGE is implicated in several other similar diseases worsened by immune system overactivity.
Suspicion that RAGE played a role in multiple sclerosis was heightened when the researchers found that the spinal cords of several patients contained high levels of RAGE and one of its ligands, S100. The patients' spinal cords also were infiltrated with four times as many RAGE-carrying cells, particularly T cells, as the spinal cords of controls.
To see if increased RAGE expression aggravated the course of multiple sclerosis or was simply a consequence of the disease, Dr. Yan turned to an animal model of the disease, the EAE mouse. EAE stands for experimental autoimmune encephalomyelitis, a disease with a pathology and symptoms similar to multiple sclerosis. The disease is induced by injecting mice with myelin proteins. The proteins activate T cells specific to myelin, and the T cells then migrate into the central nervous system to attack the myelin in the spinal cord.
The research team, guided by collaborator and senior author Dr. Hong Jiang, assistant professor of medicine, induced EAE in mice and then tried to prevent the disease's symptoms with sRAGE, a recombinant, truncated form of receptor. The RAGE blockade reduced the disease's symptoms by 80 percent, leaving most mice with only slight weakness. In contrast, all the untreated EAE mice developed paralysis and died.
Because the blockade experiments confirmed RAGE has a role in EAE, Dr. Yan then designed experiments to find out how the receptor blocker prevented disease symptoms. She tested two possibilities. In the first possibility, RAGE inactivation would prevent the generation of T cells that attack the spinal cord. In the second, receptor inactivation would prevent the migration of activated T cells into the spinal cord.
The first hypothesis was rejected when the researchers saw no difference in the activation stages of T cells in treated and untreated mice. But they did see that activated T cells did not migrate to the spinal cord in mice treated with a RAGE blocker. "The spinal cords of the treated mice also had very little inflammation," Dr. Yan says, "so we believe RAGE blockage prevents symptoms by blocking migration of T cells."
The researchers also found that only the RAGE receptors on activated T cells need to be blocked to prevent migration. T cells that Dr. Yan engineered to express a dysfunctional RAGE could not travel into the spinal cord. She speculates that by blocking RAGE on T cells, the cells can't produce chemokines and cell adhesion molecules needed for migration. More studies are planned to test this hypothesis.
Dr. Yan says the lab now is looking for small molecules that could block RAGE in patients. They may prove to be a therapeutic option someday.
This research was supported by the U.S. Public Health Service and the Multiple Sclerosis Society.