Tuzun E, Zhou L, Baehring JM, et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma

Division of Neuro-Oncology, Department of Neurology, Hospital of the University of Pennsylvania, University of Pennsylvania, 3 W. Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Acta Neuropathologica (Impact Factor: 10.76). 09/2009; 118(6):737-43. DOI: 10.1007/s00401-009-0582-4
Source: PubMed


We report the immunopathological analysis of the brain and tumor of two patients who died of anti-NMDAR-associated encephalitis, and of the tumor of nine patients who recovered. Findings included prominent microgliosis and deposits of IgG with rare inflammatory infiltrates in the hippocampus, forebrain, basal ganglia, and spinal cord. Detection of cells expressing markers of cytotoxicity (TIA, granzyme B, perforin and Fas/Fas ligand) was extremely uncommon. All tumors showed NMDAR-expressing neurons and inflammatory infiltrates. All patients’ NMDAR antibodies were IgG1, IgG2, or IgG3. No complement deposits were observed in any of the central nervous system regions examined. Overall, these findings coupled with recently reported in vitro data showing that antibodies downregulate the levels of NMDA receptors suggest that the antibody immune-response is more relevant than cytotoxic T-cell mechanisms in the pathogenesis of anti-NMDAR-associated encephalitis.

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Available from: Erdem Tüzün, Jul 11, 2014
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    • "Another feature of anti-NMDAR encephalitis is that it predominantly affects women of reproductive age (Kamei et al. 2009), and is often accompanied by ovarian teratoma (Dalmau et al. 2007, 2008). Mature-and immature-appearing neurons in ovarian teratoma ectopically express NMDARs (Sansing et al. 2007; Seki et al. 2008; Tüzün et al. 2009); this is thought to contribute to the production of anti-NMDAR antibodies. Therefore, anti- NMDAR encephalitis has been considered to be a type of paraneoplastic encephalitis (Vitaliani et al. 2005; Dalmau et al. 2007). "
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    ABSTRACT: Autoimmune synaptic encephalitis is characterized by the presence of autoantibodies against synaptic constituent receptors and manifests as neurological and psychiatric disorders. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is such an autoimmune disorder that predominantly affects young women. It is associated with antibodies against the extracellular region of the NR1 subunit of postsynaptic NMDAR. Each NMDAR functions as a heterotetrameric complex that is composed of four subunits, including NR1 and NR2A, NR2B, or NR2C. Importantly, ovarian teratoma is a typical complication of anti-NMDAR encephalitis in female patients and may contain antigenic neural tissue; however, antigenic sites remain unknown in female patients without ovarian teratoma. The purpose of this study was to investigate the expression of NMDARs in the ovum. We detected NR1 and NR2B immunoreactivity in protein fractions extracted from the bovine ovary and ova by SDS-polyacrylamide gel electrophoresis and immunoblotting analysis. Immunoprecipitates digested with trypsin were analyzed by reverse phase liquid chromatography coupled to tandem mass spectrometry. We obtained the following five peptides: SPFGRFK and KNLQDR, which are consistent with partial sequences of human NR1, and GVEDALVSLK, QPTVAGAPK, and NEVMSSK, which correspond to those of NR2A, NR2B and NR2C, respectively. Immunocytochemical analysis revealed that the bovine ovum was stained with the immunoglobulin G purified from the serum of a patient with anti-NMDAR encephalitis. Taken together, we propose that the normal ovum expresses NMDARs that have strong affinity for the disease-specific IgG. The presence of NMDARs in ova may help explain why young females without ovarian teratomas are also affected by anti-NMDAR encephalitis.
    The Tohoku Journal of Experimental Medicine 03/2015; 235(3):223-31. DOI:10.1620/tjem.235.223 · 1.35 Impact Factor
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    • "Accordingly, typical pathological findings in anti-NMDAR encephalitis consist of IgG deposition and microgliosis without complement activation and cellular inflammation. Necrotic cystic lesions have been reported in atypical forms with striatal or cortical involvement [6]; only in a few cases, minimal T- and B- cellular infiltration has been detected in the hippocampus, the forebrain, the basal ganglia and the spinal cord [7, 8]. Conversely, consistent mixed perivascular and parenchymal cellular infiltrates have been pathologically observed in a patient with anti-NMDAR antibodies and seronegative optic neuromyelitis [3]. "
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    ABSTRACT: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rapidly evolving condition that combines psychiatric and neurologic manifestations. Much remains unclear about its clinical onset and subsequent course. Although successful treatment depends on diagnosing the disorder early and therefore minimizing long-term complications, this is a difficult task owing to the atypical onset of this condition and the prolonged clinical course that has been observed in some patients. This report, illustrating a patient with slowly progressing psychiatric manifestations, unusual imaging and electrophysiological features, extends the information on varied clinical phenotypes. A 32-year-old woman suffered from an isolated depressive disorder for 4 months before undergoing psychiatric evaluation. During the following 5 months, she manifested hypersexuality, dysarthria, imbalance, dyskinesias and decreased word output. Brain magnetic resonance imaging (MRI) showed multifocal hyperintense T2/FLAIR lesions, a few contrast-enhanced, involving the corona radiata, the periventricular white matter, the deep gray nuclei, the optic nerves and the brainstem. MRI spectroscopy disclosed confluent bilateral demyelination and focal optic nerve involvement suggesting widespread encephalitis. Visual evoked potential studies indicated a demyelinating disorder. Serological screening and total body positron-emission tomography yielded negative findings for malignancies. Cerebrospinal fluid examination disclosed IgG oligoclonal bands and anti-NMDAR antibodies. Corticosteroids and intravenous immunoglobulin provided only slight improvement, whereas switching to cyclophosphamide markedly improved her neurological status. In patients with a prolonged clinical course, including psychiatric and neurological symptoms, the differential diagnosis should be anti-NMDAR encephalitis. This report expands the known disease phenotypes in this emerging condition.
    Case Reports in Neurology 02/2014; 6(1):38-43. DOI:10.1159/000358820
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    • "In fact, autoantibodies in anti-NMDA-R and -AMPA-R, GABAB-R encephalitis are of the IgG1 and IgG3 type and are thus capable of activating complement in the presence of patient plasma (containing high concentrations of complement factors). However, in none of the reported autopsy or biopsy studies complement depositions could be detected on neurons suggesting that in the presence of patient CSF (containing low concentrations of complement factors) these IgG 1 and 3 autoantibodies do not lead to relevant complement activation [6, 32, 47, 50, 63, 93]. In contrast, autoantibodies in VGKC-complex encephalitis are predominantly of the IgG4 (and IgG1) type and thus are unable to activate complement in the presence of patient plasma. "
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    ABSTRACT: Autoimmune central nervous system (CNS) inflammation occurs both in a paraneoplastic and non-paraneoplastic context. In a widening spectrum of clinical disorders, the underlying adaptive (auto) immune response targets neurons with a divergent role for cellular and humoral disease mechanisms: (1) in encephalitis associated with antibodies to intracellular neuronal antigens, neuronal antigen-specific CD8(+) T cells seemingly account for irreversible progressive neuronal cell death and neurological decline with poor response to immunotherapy. However, a pathogenic effect of humoral immune mechanisms is also debated. (2) In encephalitis associated with antibodies to synaptic and extrasynaptic neuronal cell surface antigens, potentially reversible antibody-mediated disturbance of synaptic transmission and neuronal excitability occurs in the absence of excessive neuronal damage and accounts for a good response to immunotherapy. However, a pathogenic effect of cellular immune mechanisms is also debated. We provide an overview of entities, clinical hallmarks, imaging features, characteristic laboratory, electrophysiological, cerebrospinal fluid and neuropathological findings, cellular and molecular disease mechanisms as well as therapeutic options in these two broad categories of inflammatory CNS disorders.
    Journal of Neurology 09/2012; 260(5). DOI:10.1007/s00415-012-6657-5 · 3.38 Impact Factor
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