Anti-NMDA Receptor Antibodies in Neurologic Disease (P5.179)

OBJECTIVE: To understand the role of anti-NMDAR antibodies in the pathogenesis of autoimmune encephalitis and other neurological disorders. BACKGROUND: Anti-NMDAR encephalitis, a recently discovered syndrome associated with psychosis, altered consciousness, seizures, dyskinesias, and autonomic dysfunction, is now known to be one of the most commonly identified causes of encephalitis. IgG antibodies in this syndrome may have increased affinity for the open conformation of the n-methyl-D-aspartate receptor (NMDAR), and transiently stabilize this conformation. Over the longer term, there is NMDAR hypofunction due to receptor cross-linking and internalization. Recently, anti-NMDAR IgA antibodies were found both in a progressive dementia and also in some patients with anti-NMDAR encephalitis. Anti-NMDAR antibodies have also been noted in relapse of herpes simplex encephalitis, Creutzfeldt-Jakob disease, and neuropsychiatric lupus. DESIGN/METHODS: We have developed a cell-free assay that employs soluble fragments of the NMDAR to detect anti-NDMAR antibody binding, and have used this assay, along with other established approaches, to examine epitopic diversity in syndromes associated with the production of anti-NMDAR antibodies. RESULTS: Results suggest that immune responses mapping to distinct, conformationally-dependent epitopes correlate with unique clinical features. In addition, activity-dependent changes in receptor conformation as well as changes in the clustering properties of receptors appear to affect antibody binding to receptors; preliminary data also suggests that binding results in alteration of signaling downstream of the NMDAR, such as changes in levels of phosphorylated CREB. CONCLUSIONS: These findings may point towards novel therapeutic targets in anti-NMDAR encephalitis, raise the possibility of autoimmunity in diseases not previously believed to have an immune-mediated component, and also raise the possibility of using these antibodies as tools to explore NMDAR activity and clustering. Study Supported by: NINDS T32 Trainig Grant in Neurodevelopmental Disablities (5T32NS007413-13), L. Morton Morley Funds of the Philadelphia Foundation, NINDS R21 Disclosure: Dr. Panzer has nothing to disclose. Dr. Baumann has nothing to disclose. Dr. Furukawa has nothing to disclose. Dr. Simorowski has nothing to disclose. Dr. Gleichman has nothing to disclose. Dr. Lynch has received personal compensation for activities with Retrotape, Inc. as a consultant. Dr. Lynch has received research support from Santhera Pharmaceutical, Penwest, Edison Pharmaceutical, and ViroPharma.