Antibody-Mediated Encephalitis

Dalmau, Josep; Graus, Francesc

doi:10.1056/nejmra1708712

Cited by 890 publications

(970 citation statements)

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“…Clinically, it is a severe and rare autoimmune disorder characterised by psychiatric symptoms, seizures, encephalopathy, cognitive and movement impairment 1. Among the group of AE, the most common member is the anti- N -methyl-D-aspartate receptor (NMDAR) encephalitis which is featured by autoantibodies against the GluN1 (NR1) subunit of NMDAR 2 3.…”

Section: Introductionmentioning

confidence: 99%

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

Shu

Qiu

Zheng

et al. 2019

J Neurol Neurosurg Psychiatry

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Background and objectiveAetiology and pathogenesis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus.MethodsHLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study.ResultsOur results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10−5, padj=0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02.ConclusionsThis study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.

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Section: Introductionmentioning

confidence: 99%

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

Shu

Qiu

Zheng

et al. 2019

J Neurol Neurosurg Psychiatry

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“…NMDARs are heterotetramers mainly comprising two obligatory GluN1 subunits and two GluN2 subunits, of which GluN2A and GluN2B are the main subunits present in the hippocampus (Paoletti, 2011). Anti-NMDAR encephalitis is a recently identified autoimmune synaptopathy characterized by changes in behavior, psychosis, decrease of memory, seizures, stereotyped movements, autonomic instability, and coma (Dalmau and Graus, 2018). These symptoms are accompanied by the presence of autoantibodies in cerebrospinal fluid (CSF) and serum against extracellular epitopes of the GluN1 subunit of the NMDAR (Gleichman et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

NMDA Receptor Autoantibodies in Autoimmune Encephalitis Cause a Subunit-Specific Nanoscale Redistribution of NMDA Receptors

et al. 2018

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SUMMARY Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder mediated by autoantibodies against the GluN1 subunit of the NMDAR. Patients’ antibodies cause crosslinking and internalization of NMDAR, but the synaptic events leading to depletion of NMDAR are poorly understood. Using super-resolution microscopy, we studied the effects of the autoantibodies on the nanoscale distribution of NMDAR in cultured neurons. Our findings show that, under control conditions, NMDARs form nanosized objects and patients’ antibodies increase the clustering of synaptic and extrasynaptic receptors inside the nano-objects. This clustering is subunit specific and predominantly affects GluN2B-NMDARs. Following internalization, the remaining surface NMDARs return to control clustering levels but are preferentially retained at the synapse. Monte Carlo simulations using a model in which antibodies induce NMDAR cross-linking and disruption of interactions with other proteins recapitulated these results. Finally, activation of EphB2 receptor partially antagonized the antibody-mediated disorganization of the nanoscale surface distribution of NMDARs.

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“…Limbic encephalitis associated with antibodies to leucine‐rich glioma‐inactivated 1 (LGI1) is the second most common form of the growing number of autoimmune encephalopathies (AIEs) with autoantibodies targeting central nervous system antigens . LGI1 encephalitis is characterized by generalized and partial epileptic seizures, often as faciobrachial dystonic seizures (FBDS), spatial disorientation, and amnesia, and it affects preferentially 50‐ to 70‐year‐old men.…”

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confidence: 99%

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Kornau

Kreye

Stumpf

et al. 2020

Annals of Neurology

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Objective Leucine‐rich glioma‐inactivated 1 (LGI1) encephalitis is the second most common antibody‐mediated encephalopathy, but insight into the intrathecal B‐cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. Methods We cloned, expressed, and tested antibodies from 90 antibody‐secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Results Eighty‐four percent of the ASCs and 21% of the memory B cells encoded LGI1‐reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non–ADAM22‐competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation Our data show that the patients’ intrathecal B‐cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N‐methyl‐D‐aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405–418

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Antibody-Mediated Encephalitis

Cited by 890 publications

References 50 publications

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

NMDA Receptor Autoantibodies in Autoimmune Encephalitis Cause a Subunit-Specific Nanoscale Redistribution of NMDA Receptors

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

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