Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series
By Meizan Lai, M. Huijbers, E. Lancaster, F. Graus, L. Bataller, R. Balice-Gordon, J. Cowell, J. Dalmau. Lancet Neurology, 2010
1,019 citations recorded by the source corpus.
Summary Background Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. Methods We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of Lgi1-null mice. Findings Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and Lgi1-null mice, which showed selective lack of reactivity in brains of Lgi1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan’s syndrome, and neuromyotonia. Interpretation LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. Funding National Institutes of Health, National Cancer Institute, and Euroimmun.
Subfields: Neurology, Rheumatology, Sensory Systems
View Paper: https://www.semanticscholar.org/paper/89b3d200b785ba06ea563b717711a16addfc2c8f
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Citations in the corpus
- Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis (2011, background): “It is now clear that VGKC-complex Abs, at least in patients with high titers,(3) are rarely directed against Kv1potassium channels themselves, but bind to other proteins that are tightly complexed with Kv1 subunits in situ and in detergent extracts.(3,4) Almost all patients sampled during their illn”
- Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. (2012, background): “Recent findings show that the antibodies that immunoprecipitate dendrotoxin-labelled VGKC-complexes are in fact directed to LGI1 or CASPR2 or other undefined components of the VGKC-complex (Irani et al., 2010a; Lai et al., 2010).”
- The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. (2012, neutral): “This condition infrequently associates with tumors (ie, thymomas or small-cell lung cancer), and it usually responds to immunotherapy [10].”