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

Abstract

A subset of patients with slowly progressive cognitive impairment has an underlying synaptic autoimmunity that decreases the density of NMDAR and other synaptic proteins, and alters synaptic currents. This autoimmunity can be demonstrated examining patients' serum and CSF for NMDAR IgA antibodies, identifying possible candidates for immunotherapy.

Anti-NMDA Receptor Encephalitis, Autoimmunity, and Psychosis

“…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).…”

Autoantibodies in Neuropsychiatric Disorders

“…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].…”

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

“…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.…”

“…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.…”

“…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.…”