Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: A case series

Meizan Lai, Maartje G.M. Huijbers, Eric Lancaster, Francesc Graus, Luis Bataller, Rita Balice-Gordon, John K. Cowell, Josep Dalmau

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)776-785
Number of pages10
JournalThe Lancet Neurology
Volume9
Issue number8
DOIs
StatePublished - Aug 2010

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Limbic Encephalitis
Potassium Channels
Leucine
Glioma
Voltage-Gated Potassium Channels
Antigens
Autoantigens
Antibodies
HEK293 Cells
Immunoprecipitation
Mass Spectrometry
Isaacs Syndrome
Serum
Disintegrins
National Cancer Institute (U.S.)
National Institutes of Health (U.S.)
Brain Diseases
Metalloproteases
Serologic Tests
Encephalitis

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Lai, M., Huijbers, M. G. M., Lancaster, E., Graus, F., Bataller, L., Balice-Gordon, R., ... Dalmau, J. (2010). Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: A case series. The Lancet Neurology, 9(8), 776-785. https://doi.org/10.1016/S1474-4422(10)70137-X

Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels : A case series. / Lai, Meizan; Huijbers, Maartje G.M.; Lancaster, Eric; Graus, Francesc; Bataller, Luis; Balice-Gordon, Rita; Cowell, John K.; Dalmau, Josep.

In: The Lancet Neurology, Vol. 9, No. 8, 08.2010, p. 776-785.

Research output: Contribution to journalArticle

Lai, Meizan ; Huijbers, Maartje G.M. ; Lancaster, Eric ; Graus, Francesc ; Bataller, Luis ; Balice-Gordon, Rita ; Cowell, John K. ; Dalmau, Josep. / Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels : A case series. In: The Lancet Neurology. 2010 ; Vol. 9, No. 8. pp. 776-785.
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N2 - 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.

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