Transcript anti-NMDA in Schizo.

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