ANTI-NMDA RECEPTOR ANTIBODY IN SCHIZOPHRENIA Tri Bui Shannon Sin Kelly Tran Hillary Wen PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Schizophrenia • Chronic and severe brain disorder • Characterized in DSM-V as a mental disorder that causes delusions, hallucinations, disorganized speech, behaviour, and social or occupational dysfunction Causes • Researchers still unsure what causes schizophrenia • A mixture of environmental and genetic causes The 2 Hypotheses of Schizophrenia 1. The Dopamine Hypothesis 2. The Glutamate Hypothesis The 2 Hypotheses of Schizophrenia 1. The Dopamine Hypothesis 2. The Glutamate Hypothesis -NMDA receptor hypofunction is linked to schizophrenia etiology What are NMDA receptors? • N-methyl-D-aspartate receptor • family of excitatory ionotropic glutamate receptors • • • • (iGLuRs) on neuronal membranes glutamate-gated ion channels linked to CNS important in regular functions of the brain multimeric with different subunits : NR1 Subunit + combination of NR2 &/ NR3 subunits under-activation stimulates brain complications (ex. Psychosis) Anti-NMDA receptor antibodies • studies discovered antibodies for nmda-receptor in cases of young women • some patients diagnosed with schizophrenia found to have antibodies against subunits of the receptor (NR1a/NR2b) • antibodies are of the IgG1 class (most abundant IgG subclass) Anti-NMDA receptor encephalitis • Newly discovered autoimmune disorder still not widely • • • • recognized (issue b/c if more known about, can cure more cases) inflammation of the brain caused by immune system attacking the nmda receptor Treatable with immunosuppressive therapy induce psychotic symptoms much like schizophrenia & is therefore mistakenly diagnosed as a psychological disorder rather than autoimmune disorder Diagnosis determined by detecting antibodies against the receptor How might anti-NMDAR encephalitis be initiated? • Teratoma tumors have been associated with a majority of the anti-NMDAR encephalitis cases • Theory - tumor provides the source of self antigen that induces the initial expansion of lymphocytes and the subsequent production of tumor-specific antibodies that cross-react with NMDA receptors Tumors by itself is insufficient to trigger autoimmunity • 2 main reasons: • • Incomplete antigen presentation by APCs leads to T and B cells inactivation Tumors produce immunosuppressive cytokines that induce apoptosis of auto-reactive T cells, prohibiting T cell expansion Pathogenic interaction with tumor · When an infectious agent infects the tumor, it serves as a source of ligands for pattern recognition receptors of the innate immune system including TLRs, and NOD like receptors · Activation of innate system & their respective downstream signaling pathway up-regulates the adaptive immunity, resulting in… 1.increased presentation of tumor antigens by APCs 2.breakdown of T cell tolerance mechanisms · B cells loss of tolerance and auto-reactivity · Following presentation of tumor antigen, A.Auto-reactive T helper cells help activate tumor-specific B cells, breaking B cell tolerance & inducing ClassSwitch Recombination to form IgG1 and IgG3 antibodies B.TLR ligands can also induce clonal expansion of preexisting autoimmune B cell repertoire and release proinflammatory cytokines that induces fever · Loss of cell tolerance – auto-reactivity The blood brain barrier becomes permeable to B cells Innate cytokines/TLR ligands activates transport system within the BBB, allowing auto-reactive memory B cells & plasma cells to enter the CNS · B cells clonally expand, and constitutively produce antibodies · As a result, CNS is prone to rapid clinical and respond poorly to therapeutic interventions in subsequent illness phases Experimental evidence • There’s a specific, titer dependent, reversible loss of NMDA receptors in patients with anti-NMDAR encephalitis Hughes et al (2010) “Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis” Experimental evidence • There’s a specific, titer dependent, reversible loss of NMDA receptors in patients with anti-NMDAR encephalitis Post patient’s CSF treatment Hughes et al (2010) “Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis” Experimental evidence • There’s a specific, titer dependent, reversible loss of NMDA receptors in patients with anti-NMDAR encephalitis Hughes et al (2010) “Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis” Experimental evidence • There’s a specific, titer dependent, reversible loss of NMDA receptors in patients with anti-NMDAR encephalitis Hughes et al (2010) “Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis” Experimental evidence (cont.) • NMDA receptor antagonist enhances schizophrenia-like symptoms • NMDA receptor agonist reduces schizophrenia-like symptoms • NMDA receptor subunit NR1 knockout mice – animal model for schizophrenia Practical implication • Psychiatric practice (diagnostic/treatment) • Integrating neurological testings to the diagnosis of schizophrenia – e.g. CSF analysis, EEG, testing for antineuronal antibodies • Possible immunologic specific treatment (steroids, plasmapheresis, IV IgG) “How many people currently are in psychiatric wards and nursing homes denied the relatively simple cure of steroids, plasma exchange, [or] more intense immunotherapy” Summary • Schizophrenia is a chronic and severe brain disorder marked by symptoms such as • • • • • • • hallucinations, delusions, and disorganized behaviour. N-methyl-D-aspartate receptor (NMDA receptors) - family of excitatory ionotropic glutamate receptors (iGLuRs) on neuronal membranes Various experiments showed that there’s a specific, titer dependent, and reversible loss of NMDA receptors in patients with anti-NMDAR encephalitis. anti-NMDA receptor encephalitis (an autoimmune disorder) -inflammation of the brain caused by immune system attacking the receptor, treated by immunosuppressant drugs. NMDA-R hypofunction plays a role in the pathophysiology of this immune mediated subset of schizophrenia. NMDA agonists reduces schizophrenia-like symptoms while NMDA antagonists enhances schizophrenia-like symptoms Discovery of this immune mediated mechanism calls for the need of additional testing (CSF analysis, EEG, neuronal antibodies testing) in the diagnosis of schizophrenia. Possible immunologic treatment include plasmapheresis, steroids, IV IgG (different from conventional anti-psychotics previously used to treat schizophrenia). Although the schizophrenia’s immunopathogenesis warrant further research, it has been theorized that tumors provide a source of unknown self antigen that induces the initial expansion and breakdown of tolerance mechanisms in T & B lymphocytes. Autoreactive B cells are able to cross the BBB which complicates immune responses and results in rapid CNS deterioration in anti-NMDA receptor encephalitis illness phases. References • Moghaddam B., Javitt D. (2011). “From revolution to evolution: The glutamate hypothesis of • • • • • • • schizophrenia and its implication for treatment”. Neuropsycopharmacology Reviews. 37:4-15 Peery H., Day G., Dunn S., et al. (2012) “Anti-NMDA receptor encephalitis. The disorder, the diagnosis, and the immunobiology”. Autoimmunity Reviews 11: 863-872 Coyle JT (2012) “NMDA receptor and schizophrenia: a brief history” Schizophr Bull 38(5):920-6 Deakin J, Lennox BR, Zandi MS (2014) “Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis”. Biol Psychiatry 75(4):284-91 Hughes EG, Peng X (2010) “Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis” J Neurosci 30(17):5866-75 Cheesman M., Gholkar B., Rainey K. (2014). “Anti-NMDA receptor encephalitis: an easily missed diagnosis in older patients”. Age Ageing. 43(5):725-6. Beneyto M., Huerta I., Kristiansen L., Meador-Woodruff J. (2007). “NMDA receptor and schizophrenia”. Current Opinion in Pharmacology. 7(1):48-55. Grebenciucova E., Lukas R., Mann A. (2014) “Anti-N-methyl-D-aspartate-receptor encephalitis: management, and challenges”. Ther Clin Risk Manag. 10:517-525. THE END