All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class

Castillo-Gómez, Esther; Oliveira, Bárbara; Tapken, Daniel; Bertrand, Sonia; Klein-Schmidt, Christina; Pan, Hong; Zafeiriou, Maria-Patapia; Steiner, Johann; Jurek, Betty; Trippe, Ralf H.; Prüß, Harald; Zimmermann, Wolfram‐Hubertus; Bertrand, Daniel; Ehrenreich, Hannelore; Hollmann, Michael

doi:10.1038/mp.2016.125

Cited by 124 publications

(142 citation statements)

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“…To date, studies that found NR1‐IgM have not related their presence to ongoing de novo production from recent germinal center reactions 20, 21. However, in our study, NR1‐IgM rates were surprisingly high in NMDAR‐antibody encephalitis patients and low in disease controls 22. The higher detection rate in the target population may be explained by use of live cell‐based assays, which are known to enhance sensitivity of NR1‐IgG detection 23.…”

Section: Discussioncontrasting

confidence: 57%

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

107

102

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IntroductionN‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1‐IgG production and the contribution of germinal center B cells to NR1‐IgG levels are unknown.MethodsClinical data and longitudinal paired serum NR1‐reactive IgM and IgG levels from 10 patients with NMDAR‐antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1‐specific antibodies.ResultsIn addition to disease‐defining NR1‐IgG, serum NR1‐IgM was found in 6 of 10 patients. NR1‐IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+CD27++CD38++ antibody‐secreting cells in vitro and, from 90% of patients, secreted NR1‐IgM and NR1‐IgG. Secreted levels of NR1‐IgG correlated with serum NR1‐IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1‐IgG in culture.InterpretationSerum NR1‐IgM and NR1‐IgG, alongside the consistent production of NR1‐IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1‐IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR‐antibody encephalitis. Ann Neurol 2018;83:553–561

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Section: Discussioncontrasting

confidence: 57%

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

107

102

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“…HEK293T cells (50,000) cultured at 37°C/8% CO 2 in DMEM (high glucose, Life Technologies, Carlsbad, USA) were seeded on a 35 -mm dish, grown for 3 days, and transfected with 3 µg of myc-His-tagged GluN1-1b cloned into pcDNA4/TO/myc-His A (Invitrogen, Carlsbad, USA) using Metafectene-Pro (Biontex, Munich, Germany) [10]. One day post transfection, cells were split onto five poly-Dlysine-coated coverslips in a 35 -mm dish and 1 day later, they were fixed with 5% paraformaldehyde (PFA) for 20 min, washed 5× (PBS), permeabilized with 0.1% Triton X-100 for 5 min, again washed 5× (PBS), and blocked with 5% normal goat serum (NGS; Sigma-Aldrich, Munich, Germany) for 1 h. After five PBS washes, cells were incubated with serum and monoclonal mouse anti-myc IgG (clone 9E10, Hollmann-Lab, Bochum) for 1 h, washed with 10× (PBS), incubated for 1 h with fluorescein-labeled goat anti-monkey IgM (072-11-031; KPL, Gaithersburg, USA) and AlexaFluor®594-labeled goat anti-mouse IgG (A11005; Thermo Fisher) secondary AB, and PBS washed 5×.…”

Section: Nmdar1-ab Igm Screening In Monkey Samplesmentioning

confidence: 99%

“…To assess AB functionality, human IPSC-derived neurons were exposed to dialyzed serum [10]. For each species, arbitrarily selected seronegative (N = 1) and seropositive samples (N = 2-3) were analyzed.…”

Section: Endocytosis Assaymentioning

confidence: 99%

“…The reported syndrome, reflecting typical NMDAR1 antagonistic actions, consisted of psychosis, epileptic seizures, dyskinesia, cognitive decline, reduced consciousness, and autonomic dysregulation [1][2][3][4]. However, work on >5000 individuals, healthy or affected by different diseases, consistently revealed overall comparable age-dependent seroprevalence of functional NMDAR1-AB of all Ig classes, nurturing serious doubts regarding a purely pathological role of NMDAR1-AB of any Ig class [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Despite this apparent "physiological autoimmunity", no report exists that systematically screened mammals other than humans for the presence of NMDAR1-AB. In recent work, we found that all naturally occurring NMDAR1-AB are functional and thus have pathogenic potential irrespective of epitope and Ig class [10]. Pathophysiological significance may emerge in conditions of compromised blood-brain barrier (BBB), for instance, upon injury, infection, inflammation, or genetic predisposition (APOE4 haplotype), which then allows substantial access of circulating NMDAR1-AB to the brain where they act as NMDAR antagonists [5,9,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model

Pan

Oliveira

Saher

et al. 2018

Neurology, Psychiatry and Brain Research

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Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE −/− and ApoE +/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE −/− mice, characterized by an open blood-brain barrier, but not in their ApoElittermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE −/− and ApoE +/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own.

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Association Between Neuronal Autoantibodies and Cognitive Impairment in Patients With Lung Cancer

et al. 2021

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IMPORTANCE Paraneoplastic neurological syndromes are associated with neuronal autoantibodies, and some of these autoantibodies are associated with neuropsychological symptoms. The most common underlying tumor is lung cancer. The association of neuronal autoantibodies with cognitive deficits has not been systematically investigated in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).OBJECTIVE To assess the frequency of neuronal autoantibodies in patients with lung cancer and analyze their association with cognitive function.DESIGN, SETTING, AND PARTICIPANTS This prospective, cross-sectional study included 167 patients with lung cancer (both SCLC and NSCLC) recruited at a single lung cancer center in Berlin, Germany, between June 2015 and April 2016. Detailed neuropsychological testing was performed in a carefully selected subgroup of 97 patients (from which patients with potential confounding factors were excluded). Investigators were blinded to patients' autoantibody status and cognitive test results. Data were analyzed from May 2016 to December 2019. MAIN OUTCOMES AND MEASURESPrevalence of neuronal autoantibodies and their association with cognitive impairment. The evaluation of autoantibodies as potential risk factors for cognitive impairment was performed using bayesian logistic regression models. RESULTS Among 167 patients with lung cancer (median age, 66.0 years [interquartile range, 59.0-72.0 years]; 105 men [62.9%]), 127 had NSCLC, and 40 had SCLC. Brain-directed autoantibodies were detected in 61 of 167 patients (36.5%); 33 patients (19.8%) had known autoantibodies and 28 patients (16.8%) had autoantibodies against currently unknown antigens that were detected through immunohistochemical analysis. Cognitive impairment was found in 65 of 97 patients (67.0%). Among patients with SCLC, the odds of cognitive impairment for those with any autoantibodies was 11-fold higher (odds ratio [OR], 11.0; 95% credible interval [CrI], 1.2-103.6) than that of autoantibody-negative patients, and the increased odds were independent of age, sex, and neurological deficit. Among patients with NSCLC, those with immunoglobin A autoantibodies targeting the N-methyl-D-aspartate receptor had a relevantly increased odds of verbal memory deficits (OR, 182.8; 95% CrI,. Autoantibodies against currently unknown antigens were also associated with increased odds of cognitive impairment (OR, 2.8; 95% CrI, 0.6-12.1). CONCLUSIONS AND RELEVANCEIn this prospective, cross-sectional study, more than one-third of patients with lung cancer had neuronal autoantibodies that were found to be associated with cognitive impairment. These autoantibodies might represent a potentially treatable mechanism of immune-mediated cognitive impairment among patients with lung cancer.

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All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class

Cited by 124 publications

References 41 publications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model

Association Between Neuronal Autoantibodies and Cognitive Impairment in Patients With Lung Cancer

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