Immunopathogenesis of anti-NMDA receptor encephalitis

There are two known triggers of anti-NMDA receptor encephalitis: a tumor (usually ovarian teratoma) and herpes simplex encephalitis. The process between either of these triggers and the CNS production of antibodies is not clear; however, studies have confirmed de novo intrathecal synthesis of antibodies and CNS plasma cells after recovery from herpes simplex encephalitis. It is postulated that NMDA receptors expressed by nervous tissue within the tumor or released by viral-induced neuronal destruction, either in soluble form or loaded in antigen-presenting cells, is transported to regional lymph nodes (eg, pelvic-abdominal in ovarian teratoma or deep cervical lymph nodes in herpes simplex encephalitis) and presented to the immunologic system. Naive B cells exposed to NMDA receptors by antigen-presenting cells, and with cooperation of CD41 T-cells, become antigen-experienced memory B cells, differentiating into antibody-producing plasma cells. Memory B cells reach the brain by crossing the blood-brain barrier or via the choroidal plexus. In the brain, these B cells undergo re-stimulation, antigen-driven affinity maturation, clonal expansion, and differentiation into antibody-producing plasma cells. In tumors other than teratoma (eg, without nervous tissue within the tumor itself), the antigen is aberrantly expressed by the neoplastic cells. Of note, in approximately 50% of the patients the immunologic trigger of the disease is unknown. Reproduced with permission from Dalmau J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology 2016;87(23):2471-82.