The initial focus of this grant was paraneoplastic immunity to Ma proteins. We identified this disorder in men with testicular tumors and brainstem and limbic encephalitis (LE) who developed antibodies to neuronal proteins expressed by the tumors. These antibodies served to isolate the antigens (Ma1-3), assisted in characterizing the disorder (Ma-encephalitis), and led to the development of diagnostic tests currently used worldwide. As the work proceeded we identified patients who were thought to have Ma antibodies on clinical grounds but when tested, had other antibodies. A recent breakthrough has been the discovery of a life- threatening, but treatment-responsive disorder and the identification of the autoantigens, leading to a successful treatment approach. Patients are usually young women with ovarian teratoma who develop prominent psychiatric symptoms, seizures, dyskinesias, autonomic instability, and hypoventilation often requiring prolonged ventilatory support. All of these patients had antibodies to neuronal cell surface antigens (enriched in the hippocampus and ovarian teratoma) that we identified as NR1/NR2 heteromers of the NMDA receptor (NMDAR). Although this disorder is more life-threatening than other LE, patients are much more responsive to IgG-depleting treatments and tumor removal. Clinical and immunopathological data as well as functional analysis of the effects of patients'antibodies on hippocampal neuronal cultures support the concept that the disorder is mediated by the NMDAR antibodies. Given the importance of the NMDAR in learning, memory and behavior, the discovery of this disorder provides a human model of immune mediated NMDAR dysfunction, and reagents (patients'antibodies) that can be used to determine the epitope targets and model the disease in animals. We have also identified another category of treatment-responsive LE;preliminary findings show that the antigens are highly enriched in the dendrites and synaptic regions of the hippocampus. Based on these data we postulate the occurrence of two groups of autoimmune LE;one group (prototype: Ma-encephalitis) includes disorders related to intracellular antigens;the other group (prototype: NMDAR- encephalitis) includes disorders related to cell membrane antigens. While disorders of the first group associate with cancer, brain cytotoxic T-cell infiltrates, and variable response to treatment, the second group of disorders associate less frequently with cancer, appear to be mediated by antibodies, and usually respond to IgG-depleting strategies. The three specific aims of this competing renewal application are: 1) to fully define the clinical-immunological phenotypes of LE and repertoire of NR2 (NMDAR) antigens;2) to map the epitope regions of NR2 subunits of the NMDAR and isolate other hippocampal antigens, and 3) to determine whether antibodies to NR1/NR2 heteromers of the NMDAR cause symptoms of LE in a mouse model and produce electrophysiological abnormalities in slices of hippocampus. This work will define a link between NMDAR antibodies and human disease, and will impact the management of LE beyond the paraneoplastic disorders.
These studies will lead to the development of rapid serological and clinical diagnostic tests that will facilitate the recognition and treatment of patients with some types of immune mediated neurological disorders. If not recognized and treated appropriately, some of these disorders can be fatal and therefore tools that facilitate diagnosis are critical. In addition, the proposed studies will produce an animal model that will help to better understand, recognize, and treat immunological diseases that affect memory, behavior and cognition.
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