TY - JOUR
T1 - Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels
T2 - A case series
AU - Lai, Meizan
AU - Huijbers, Maartje G.M.
AU - Lancaster, Eric
AU - Graus, Francesc
AU - Bataller, Luis
AU - Balice-Gordon, Rita
AU - Cowell, John K.
AU - Dalmau, Josep
N1 - Funding Information:
This work was supported in part by grants from the National Institutes of Health and National Cancer Institute ( RO1CA107192, 1RC1NS068204-01 [JD and RB-G], NS046706 [JC]) and by a research grant from Euroimmun, Luebeck, Germany (JD). Thanks to Yuko Fukata and Masaki Fukata (National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan) for kindly providing plasmids containing ADAM22 or ADAM23, to Steven Scherer (University of Pennsylvania, PA, USA) for providing plasmids containing Kv1.1 and Kv1.4, and to Elior Peles (The Weizmann Institute of Science, Israel) for providing the plasmid containing CASPR2. We thank Eugenia M Martínez Hernández (Laboratory of Neuro-Oncology, Department of Neurology, University of Pennsylvania, PA, USA) for assisting in the immunoblot studies; Michael Geschwind (Department of Neurology, Memory and Aging Center, University of California, San Francisco Medical Center, San Francisco, CA, USA), Takahiro Iizuka (Department of Neurology, School of Medicine, Kitasato University, Sagamihara, Japan), Yoko Takiyama (Department of Medicine, School of Medicine, Kitasato University, Tokyo, Japan), Vanda A Lennon (Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA) and Sabrina Matà (Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy) for providing samples and information from patients. We thank the physicians who provided clinical information. We also thank the patients and their families.
PY - 2010/8
Y1 - 2010/8
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.
AB - 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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U2 - 10.1016/S1474-4422(10)70137-X
DO - 10.1016/S1474-4422(10)70137-X
M3 - Article
C2 - 20580615
AN - SCOPUS:77955338789
SN - 1474-4422
VL - 9
SP - 776
EP - 785
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 8
ER -