ObjectiveAutoimmune encephalitis is most frequently associated with anti‐NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody‐producing clones, and characterize their antibody signatures in recombinant form.MethodsPatients with recent onset typical anti‐NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy‐ (IgH) and light‐chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.ResultsIntrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen‐driven intrathecal immune response. Consistently, a single recombinant human GluN1‐specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.InterpretationA CNS‐specific humoral immune response is present in anti‐NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti‐NMDAR encephalitis as a humorally mediated autoimmune disease.
IntroductionSubspecies of apolipoproteins can be defined by fractionating apolipoproteins based on the presence and absence of coexisting apolipoproteins.MethodsWe determined age- and sex-adjusted correlations of enzyme-linked immunosorbent assay–measured plasma and cerebrospinal fluid (CSF) apolipoproteins (apoA-I, apoC-III, apoE, and apoJ) or apolipoprotein subspecies (apoA-I with and without apoC-III, ApoE, or apoJ; apoE with and without apoC-III or apoJ) in 22 dementia-free participants.ResultsCSF apoE did not correlate with plasma apolipoproteins or their subspecies. CSF apoJ correlated most strongly with plasma apoA-I without apoJ (r = 0.7). CSF apoA-I correlated similarly strong with plasma total apoA-I and all apoA-I subspecies (r ≥ 0.4) except for apoA-I with apoE (r = 0.3) or apoA-I with apoJ (r = 0.3). CSF apoC-III was most strongly correlated with plasma apoA-I with apoC-III (r = 0.7).DiscussionCSF levels of some apolipoproteins implicated in the pathophysiology of dementia might be better approximated by specific plasma apolipoprotein subspecies than total plasma concentrations.
ObjectiveTo report an unusual clinical phenotype of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis and describe associated neuropathologic findings.MethodsWe retrospectively investigated 3 AMPAR encephalitis patients with autoimmune global hippocampal amnesia using comprehensive cognitive and neuropsychologic assessment, antibody testing by in-house tissue-based and cell-based assays, and neuropathologic analysis of brain autopsy tissue including histology and immunohistochemistry.ResultsThree patients presented with acute-to-subacute global amnesia without affection of cognitive performance, attention, concentration, or verbal function. None of the patients had epileptic seizures, change of behavior, personality changes, or psychiatric symptoms. The MRI was normal in 1 patient and showed increased fluid-attenuated inversion recovery/T2 signal in the hippocampus in the other 2 patients. Two patients showed complete remission after immunotherapy. The one patient who did not improve had an underlying adenocarcinoma of the lung and died 3.5 months after disease onset because of tumor progression. Neuropathologic analysis of the brain autopsy revealed unilateral hippocampal sclerosis accompanied by mild inflammatory infiltrates, predominantly composed of T lymphocytes, and decrease of AMPAR immunoreactivity.ConclusionAMPAR antibodies usually associate with limbic encephalitis but may also present with immune responsive, acute-to-subacute, isolated hippocampal dysfunction without overt inflammatory CSF or MRI changes.
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