We think we understand why some manifestations are transient and some are not.
Manhasset, NY (Vocus) November 5, 2010
Many patients with systemic lupus erythematosus (SLE) suffer from a variety of neuropsychiatric problems and scientists at the Feinstein Institute for Medical Research have been trying to understanding the mechanism that underlies these devastating problems. Now, Betty Diamond, MD, head of the Center for Autoimmune and Musculoskeletal Disorders at the Feinstein Institute, has collaborated with colleagues at the Burke Cornell Medical Research Institute to identify two distinct mechanisms that explain the how lupus autoantibodies alter brain function and led to such a wide array of neuropsychiatric complaints.
Patients with lupus, an autoimmune disease that targets many different organs of the body, including the brain, generate autoantibodies that frequently bind double-stranded DNA and cross react with specific glutamate receptors that are toxic to brain cells. The autoantibodies can mediate the cognitive and emotional problems (depression, memory problems and confusion) that are common among lupus patients.
Patricio Huerta, PhD, and Bruce T. Volpe, MD, of the Burke Research Institute have worked with the Diamond lab at the Feinstein to figure out what is going at the level of the neuron that could help explain why the symptoms are so varied. They report in the latest issue of PNAS that the anti-DNA antibody binds to open receptors and that the antibody to the glutamate NMDA receptor only targets activated neurons. At low concentrations, the antibodies augment (NMDA) excitatory post synaptic potentials and at high concentrations they alter mitochondria permeability and cause cell death. This could explain, said Dr. Diamond, why the severity of the symptoms differs from patient to patient.
“This finding helps explain why some cognitive problems are transient and some are permanent,” she said. “Low concentrations of antibody cause transient problems and high concentrations (that lead to cell death) cause life-long problems.”
While this part of the research was conducted in lab dishes, they also studied cerebrospinal fluid samples from lupus patients and found that the levels from low to high concentrations are associated with their symptoms. “We think we understand why some manifestations are transient and some are not,” said Dr. Diamond.
The scientists have worked with medicinal chemists at the Feinstein Institute on the development of drugs that block the antibody from binding to the NMDA receptor. There is now work underway in laboratory models to test whether these can prevent the devastating neuropsychiatric symptoms of lupus.
About The Feinstein Institute for Medical Research
Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in cancer, leukemia, lymphoma, Parkinson's disease, Alzheimer’s disease, psychiatric disorders, substance abuse, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, neuroimmunology, and medicinal chemistry. Feinstein researchers are developing new drugs and drug targets, and producing results where science meets the patient, annually enrolling some 10,000 subjects into clinical research programs.