Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability.
ADAM Proteins
/ drug effects
Aged
Animals
Antibodies, Monoclonal
/ cerebrospinal fluid
Autoantibodies
/ cerebrospinal fluid
CA3 Region, Hippocampal
/ physiology
Cells, Cultured
Encephalitis
/ cerebrospinal fluid
Female
Hashimoto Disease
/ cerebrospinal fluid
Humans
Immunoglobulin Isotypes
Intracellular Signaling Peptides and Proteins
/ antagonists & inhibitors
Male
Mice
Mice, Knockout
Middle Aged
Nerve Tissue Proteins
/ drug effects
Neurons
/ physiology
Rats
Synaptic Transmission
/ drug effects
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
02
04
2019
revised:
30
12
2019
accepted:
30
12
2019
pubmed:
5
1
2020
medline:
4
8
2020
entrez:
5
1
2020
Statut:
ppublish
Résumé
Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.
Substances chimiques
Antibodies, Monoclonal
0
Autoantibodies
0
Immunoglobulin Isotypes
0
Intracellular Signaling Peptides and Proteins
0
LGI1 protein, human
0
Lgi1 protein, mouse
0
Nerve Tissue Proteins
0
ADAM Proteins
EC 3.4.24.-
ADAM22 protein, human
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
405-418Informations de copyright
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
Références
Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133:2734-2748.
Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9:776-785.
Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017;97:839-887.
van Sonderen A, Petit-Pedrol M, Dalmau J, et al. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol 2017;13:290-301.
Crisp SJ, Kullmann DM, Vincent A. Autoimmune synaptopathies. Nat Rev Neurosci 2016;17:103-117.
Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018;378:840-851.
Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892-900.
Finke C, Pruss H, Heine J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 2017;74:50-59.
Gadoth A, Zekeridou A, Klein CJ, et al. Elevated LGI1-IgG CSF index predicts worse neurological outcome. Ann Clin Transl Neurol 2018;5:646-650.
Binks S, Varley J, Lee W, et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain 2018;141:2263-2271.
Kim TJ, Lee ST, Moon J, et al. Anti-LGI1 encephalitis is associated with unique HLA subtypes. Ann Neurol 2017;81:183-192.
van Sonderen A, Roelen DL, Stoop JA, et al. Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4. Ann Neurol 2017;81:193-198.
Mueller SH, Farber A, Pruss H, et al. Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann Neurol 2018;83:863-869.
Fukata Y, Adesnik H, Iwanaga T, et al. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 2006;313:1792-1795.
Yamagata A, Miyazaki Y, Yokoi N, et al. Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22. Nat Commun 2018;9:1546.
Lovero KL, Fukata Y, Granger AJ, et al. The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function. Proc Natl Acad Sci U S A 2015;112:E4129-E4137.
Schulte U, Thumfart JO, Klocker N, et al. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron 2006;49:697-706.
Yu YE, Wen L, Silva J, et al. Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability. Hum Mol Genet 2010;19:1702-1711.
Fukata Y, Lovero KL, Iwanaga T, et al. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A 2010;107:3799-3804.
Chabrol E, Navarro V, Provenzano G, et al. Electroclinical characterization of epileptic seizures in leucine-rich, glioma-inactivated 1-deficient mice. Brain 2010;133:2749-2762.
Seagar M, Russier M, Caillard O, et al. LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. Proc Natl Acad Sci U S A 2017;114:7719-7724.
Lalic T, Pettingill P, Vincent A, et al. Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission. Epilepsia 2011;52:121-131.
Petit-Pedrol M, Sell J, Planaguma J, et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 2018;141:3144-3159.
Romoli M, Krashia P, Sen A, et al. Hippocampal epileptogenesis in autoimmune encephalitis. Ann Clin Transl Neurol 2019;6:2261-2269.
Kreye J, Wenke NK, Chayka M, et al. Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain 2016;139:2641-2652.
Malviya M, Barman S, Golombeck KS, et al. NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody. Ann Clin Transl Neurol 2017;4:768-783.
Tiller T, Meffre E, Yurasov S, et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 2008;329:112-124.
Wardemann H, Yurasov S, Schaefer A, et al. Predominant autoantibody production by early human B cell precursors. Science 2003;301:1374-1377.
Murugan R, Buchauer L, Triller G, et al. Clonal selection drives protective memory B cell responses in controlled human malaria infection. Sci Immunol 2018;3. pii: eaap8029.
Wenke NK, Kreye J, Andrzejak E, et al. N-methyl-D-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit. Ann Neurol 2019;85:771-776.
Ohkawa T, Fukata Y, Yamasaki M, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013;33:18161-18174.
Rost BR, Schneider F, Grauel MK, et al. Optogenetic acidification of synaptic vesicles and lysosomes. Nat Neurosci 2015;18:1845-1852.
Gray D. A role for antigen in the maintenance of immunological memory. Nat Rev Immunol 2002;2:60-65.
Arino H, Armangue T, Petit-Pedrol M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology 2016;87:759-765.
Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012;72:241-255.
Storm JF. Temporal integration by a slowly inactivating K+ current in hippocampal neurons. Nature 1988;336:379-381.
Metz AE, Spruston N, Martina M. Dendritic D-type potassium currents inhibit the spike afterdepolarization in rat hippocampal CA1 pyramidal neurons. J Physiol 2007;581:175-187.
Bekkers JM, Delaney AJ. Modulation of excitability by alpha-dendrotoxin-sensitive potassium channels in neocortical pyramidal neurons. J Neurosci 2001;21:6553-6560.
Castillo-Gomez E, Kastner A, Steiner J, et al. The brain as immunoprecipitator of serum autoantibodies against N-methyl-D-aspartate receptor subunit NR1. Ann Neurol 2016;79:144-151.
Marquetand J, van Lessen M, Bender B, et al. Slowly progressive LGI1 encephalitis with isolated late-onset cognitive dysfunction: a treatable mimic of Alzheimer's disease. Eur J Neurol 2016;23:e28-e29.
Reintjes W, Romijn MD, Hollander D, et al. Reversible dementia: two nursing home patients with voltage-gated potassium channel antibody-associated limbic encephalitis. J Am Med Dir Assoc 2015;16:790-794.
Geiger JR, Jonas P. Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons. Neuron 2000;28:927-939.
Kole MH, Letzkus JJ, Stuart GJ. Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron 2007;55:633-647.
Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348-356.
Kues WA, Wunder F. Heterogeneous expression patterns of mammalian potassium channel genes in developing and adult rat brain. Eur J Neurosci 1992;4:1296-1308.
Rhodes KJ, Strassle BW, Monaghan MM, et al. Association and colocalization of the Kvbeta1 and Kvbeta2 beta-subunits with Kv1 alpha-subunits in mammalian brain K+ channel complexes. J Neurosci 1997;17:8246-8258.
Boillot M, Lee CY, Allene C, et al. LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development. Sci Rep 2016;6:21769.
Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010;30:5866-5875.
Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009;65:424-434.