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AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location
Author(s) -
Lai Meizan,
Hughes Ethan G.,
Peng Xiaoyu,
Zhou Lei,
Gleichman Amy J.,
Shu Huidy,
Matà Sabrina,
Kremens Daniel,
Vitaliani Roberta,
Geschwind Michael D.,
Bataller Luis,
Kalb Robert G.,
Davis Rebecca,
Graus Francesc,
Lynch David R.,
BaliceGordon Rita,
Dalmau Josep
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21589
Subject(s) - ampa receptor , limbic encephalitis , antibody , antigen , glutamate receptor , hippocampal formation , immunocytochemistry , encephalitis , receptor , immunology , immunoprecipitation , medicine , biology , pathology , autoantibody , virus
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 α‐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. Interpretation 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. Ann Neurol 2009;65:424–434