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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    • "Although after 10–15 days macrophages and lymphocytes are the predominant populations, the progressive necrosis leads to further neutrophil infiltration, which would be supported by our findings[22]. Histopathological data for immune-mediated encephalitis are limited, but small series describe either no leucocyte infiltration or scanty lymphocytes without neutrophils, and in a subset cytotoxic T lymphocytes may predominate[16,363738. Similar observations have been made in rodent models[37]. "
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    ABSTRACT: Background: Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause. Methods: We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology. Results: Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001). Conclusions: Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "Further studies focusing particularly on the cognitive deficits have shown that there is a long-term morbidity in this disorder, with a good outcome for the patient dependent on early and aggressive treatment (Finke et al. 2012). The brains of these patients show few inflammatory cells (mostly T cells) (Tuzun et al. 2009;Camdessanche et al. 2011;Martinez-Hernandez et al. 2011;Bien et al. 2012) and magnetic resonance imaging (MRI), and pathological studies show that the neuronal loss in most cases is remarkably mild (Dalmau et al. 2007;Iizuka et al. 2010;Bien et al. 2012). The antibodies have been shown to be pathogenic, at least in vitro. "
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    ABSTRACT: This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.
    Full-text · Article · Dec 2015 · Cold Spring Harbor Perspectives in Medicine
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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.
    Preview · Article · Mar 2015 · The Tohoku Journal of Experimental Medicine
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