title: AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
abstract: OBJECTIVE
  To report the clinical and immunological features of a novel autoantigen related to limbic encephalitis (LE) and the effect of patients' antibodies on neuronal cultures.
  
  
  METHODS
  We conducted clinical analyses of 10 patients with LE. Immunoprecipitation and mass spectrometry were used to identify the antigens. Human embryonic kidney 293 cells expressing the antigens were used in immunocytochemistry and enzyme-linked immunoabsorption assay. The effect of patients' antibodies on cultures of live rat hippocampal neurons was determined with confocal microscopy.
  
  
  RESULTS
  Median age was 60 (38-87) years; 9 were women. Seven had tumors of the lung, breast, or thymus. Nine patients responded to immunotherapy or oncological therapy, but neurological relapses, without tumor recurrence, were frequent and influenced the long-term outcome. One untreated patient died of LE. All patients had antibodies against neuronal cell surface antigens that by immunoprecipitation were found to be the glutamate receptor 1 (GluR1) and GluR2 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Human embryonic kidney 293 cells expressing GluR1/2 reacted with all patients' sera or cerebrospinal fluid, providing a diagnostic test for the disorder. Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal.
  
  
  CONCLUSIONS
  Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment responsive, and has a tendency to relapse. Our findings support an antibody-mediated pathogenesis in which patients' antibodies alter the synaptic localization and number of AMPARs.
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Meizan
authors.initials: M
authors.lastname: Lai
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Hughes
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Peng
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Gleichman
authors.forename: Huidy
authors.initials: H
authors.lastname: Shu
authors.forename: Sabrina
authors.initials: S
authors.lastname: Matà
authors.forename: Daniel
authors.initials: D
authors.lastname: Kremens
authors.forename: Roberta
authors.initials: R
authors.lastname: Vitaliani
authors.forename: Michael D
authors.initials: MD
authors.lastname: Geschwind
authors.forename: Luis
authors.initials: L
authors.lastname: Bataller
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kalb
authors.forename: Rebecca
authors.initials: R
authors.lastname: Davis
authors.forename: Francesc
authors.initials: F
authors.lastname: Graus
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.forename: Rita
authors.initials: R
authors.lastname: Balice-Gordon
authors.forename: Josep
authors.initials: J
authors.lastname: Dalmau