IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment

Prüß, Harald; Höltje, Markus; Maier, Nikolaus; Gomez, Alloysius; Buchert, Ralph; Harms, Lutz; Ahnert‐Hilger, Gudrun; Schmitz, Dietmar; Terborg, C.; Kopp, Ute A.; Klingbeil, Christine; Probst, Christian; Köhler, Stephan; Schwab, Jan M.; Stoecker, Winfried; Dalmau, Josep; Wandinger, Klaus‐Peter

doi:10.1212/wnl.0b013e318258300d

Cited by 129 publications

(137 citation statements)

References 26 publications

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“…Importantly, anti-NMDAR encephalitis and the associated psychotic symptoms are caused specifically by IgG antibodies recognizing the GluN1 subunit of the NMDAR (Dalmau et al, 2008). The clinical significance of IgG antibodies that target other NMDAR subunits or of IgA or IgM subtypes recognizing NMDARs is unknown, though connections have been made between these subtypes and dementia and viral encephalitis (Doss et al, 2014;Prüss et al, 2012aPrüss et al, , 2012b. Examination of serum obtained at symptom onset from 80 patients with new-onset psychosis who 1 year later met criteria for schizophrenia-spectrum illness revealed no presence of IgG GluN1 antibodies in either patients or controls (Masdeu et al, 2012).…”

Section: Anti-nmdar Antibodies and Psychosismentioning

confidence: 99%

Anti-NMDA Receptor Encephalitis, Autoimmunity, and Psychosis

Kayser

Dalmau

2016

FOC

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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms -and in particular psychosis -early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in anti-NMDAR encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia.

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Section: Anti-nmdar Antibodies and Psychosismentioning

confidence: 99%

Anti-NMDA Receptor Encephalitis, Autoimmunity, and Psychosis

Kayser

Dalmau

2016

FOC

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“…This subunit was also recognized by IgA or IgM [160] but not specifically related with schizophrenia, since they were also present in other pathologies and in control individuals [121,159]. IgA autoantibodies to NMDA-R (but not IgG) were described in a cognitive dysfunction cohort where they are thought to induce decreased NMDA-R expression and NMDA-R mediated currents in neuronal cell cultures [120].…”

Section: Psychotic Disordersmentioning

confidence: 99%

Autoantibodies in Neuropsychiatric Disorders

et al. 2016

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Abstract:Little is known about the etiology of neuropsychiatric disorders. The identification of autoantibodies targeting the N-methyl-D-aspartate receptor (NMDA-R), which causes neurological and psychiatric symptoms, has reinvigorated the hypothesis that other patient subgroups may also suffer from an underlying autoimmune condition. In recent years, a wide range of neuropsychiatric diseases and autoantibodies targeting ion-channels or neuronal receptors including NMDA-R, voltage gated potassium channel complex (VGKC complex), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), γ-aminobutyric acid receptor (GABA-R) and dopamine receptor (DR) were studied and conflicting reports have been published regarding the seroprevalence of these autoantibodies. A clear causative role of autoantibodies on psychiatric symptoms has as yet only been shown for the NMDA-R. Several other autoantibodies have been related to the presence of certain symptoms and antibody effector mechanisms have been proposed. However, extensive clinical studies with large multicenter efforts to standardize diagnostic procedures for autoimmune etiology and animal studies are needed to confirm the pathogenicity of these autoantibodies. In this review, we discuss the current knowledge of neuronal autoantibodies in the major neuropsychiatric disorders: psychotic, major depression, autism spectrum, obsessive-compulsive and attention-deficit/hyperactivity disorders.

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“…The stimuli can cause somatic mutation and expansion, which might generate a population of B cells with new antigen specificities. Bennett et al 129 Vaknin-Dembinsky et al 130 Nit ßescu et al 131 Nico et al 132 Multiple sclerosis Menge et al 69 Solly et al 54 Berger et al 71 Rasmussen's encephalitis 135 Popp et al 136 Burbelo et al 137 Skorstad et al 138 Encephalitis (ANNA-1 mediated) 143 Buckanovich et al 144 Pittock et al 145 Brainstem encephalitis (ANNA-3 mediated) Pr€ uss et al 72 Dalmau et al 148 Takai et al 149 Verhelst et al 150 Gleichman et al 151 Lancaster et al 160 Stengel et al 161 Abou-Zeid et al 162 Morvan's syndrome symptoms include psychiatric symptoms, seizures, insomnia, dysautonomia, neuromyotonia combined with cerebellitis. AGNA, anti-glial/neuronal immunoglobulin G1/3 antibodies; ANNA, anti-Neuronal Nuclear antibody; APS, antiphospholipid syndrome; AQP4, aquaporin-4; BBB, blood-brain barrier; CASPR2, the contacting associated protein-2; EBV, Epstein-Barr virus; GABA, gamma-aminobutyric acid; GABAa/b, metabotropic transmembrane receptors for gamma-aminobutyric acid that are linked through G-proteins to potassium channels; GAD65, glutamic acid decarboxylase 65; GAD67, glutamic acid decarboxylase 67; GluN1, glycine-binding subunit of the N-methyl- means of molecular mimicry theory, one of the most plausible explanations.…”

Section: Breakdown Of Tolerance: Loss Of Immune Homeostasis In the Cnsmentioning

confidence: 99%

“…73 Hence, they could also herald patterns of susceptibility to CNS autoimmunity even before disease onset, as it was shown for other organ-specific autoimmune diseases. 72,74,75 Besides all previous findings on autoantibodies and CNS autoimmunity, there are additional events that are necessary to occur before disease onset.…”

mentioning

confidence: 91%

“…Such antibodies also caused a dramatic decrease of the levels of NMDA proteins in mouse hippocampal neurons in vitro. 72 Otherwise, autoantibody networks might be used as clues on an individual′s profile of a personal immune state organization throughout disease or health, as initially proposed by Irun Cohen. 73 Hence, they could also herald patterns of susceptibility to CNS autoimmunity even before disease onset, as it was shown for other organ-specific autoimmune diseases.…”

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confidence: 99%

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Mechanisms of autoimmunity in the central nervous system: Disturbance of natural autoimmunity, infectious agents, cell contribution and antibody signatures

Ortega-Hernandez

2013

Clinical & Exp Neuroim

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Autoimmunity in the central nervous system (CNS) seems to be a physiological process that might normally occur from the very early stages of fetal development. There is some evidence suggesting that CNS autoimmunity could participate in brain structuring, early antigen recognition and immune tolerance. Interestingly, clues to the occurrence of such early events can be discovered in cord blood samples from newborns and peripheral blood, as well as cerebrospinal fluid samples from adults by means of antibody profiling, through antigen microarray technology. In the past, results from those studies raised the possibility for the existence of a physiological autoantibody network recognizing self-key antigens, as proposed by Irun Cohen many years ago. After examining those findings, I suggest the existence of a specific autoantibody network recognizing resident antigens, which would eventually behave as a two-sided sword in the CNS. It might act as a framework for the organization of local immune homeostasis, which is necessary for the maintenance of neurophysiological processes. On the contrary, it might also participate in the pathogenesis of abnormal autoimmunity after the loss of tolerance to resident antigens. The disturbance of this synchronic homeostasis by environmental stimuli might trigger abnormal reactivity, influenced by favorable genetic conditions. In this regard, the evidence supporting some cutting-edge concepts that are intended to comprehensively characterize the molecular and cellular mechanisms likely implicated in abnormal CNS autoimmunity (primarily in multiple sclerosis) is presented. Finally, the usefulness of the detection of specific disease-associated autoantibodies and autoantibody profiling as clinical tools is also approached.

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IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment

Cited by 129 publications

References 26 publications

Anti-NMDA Receptor Encephalitis, Autoimmunity, and Psychosis

Anti-NMDA Receptor Encephalitis, Autoimmunity, and Psychosis

Autoantibodies in Neuropsychiatric Disorders

Mechanisms of autoimmunity in the central nervous system: Disturbance of natural autoimmunity, infectious agents, cell contribution and antibody signatures

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