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Human cerebrospinal fluid monoclonal LGI1 autoantibodies increase neuronal excitability

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Item Type:Article
Title:Human cerebrospinal fluid monoclonal LGI1 autoantibodies increase neuronal excitability
Creators Name:Kornau, H.C. and Kreye, J. and Stumpf, A. and Fukata, Y. and Parthier, D. and Sammons, R.P. and Imbrosci, B. and Kurpjuweit, S. and Kowski, A.B. and Fukata, M. and Prüss, H. and Schmitz, D.
Abstract:OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediatedencephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype dis-tribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. METHODS: We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from thecerebrospinalfluid (CSF) of several patients with LGI1 encephalitis. RESULTS: Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereasreactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had under-gone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with itsreceptor 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 excit-ability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation: Our data show that the patients’intrathecal B-cell autoimmune response is dominated by LGI1 anti-bodies 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 reper-toire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides arevery distinct entities.
Keywords:ADAM Proteins, Autoantibodies, Cultured Cells, Encephalitis, Hashimoto Disease, Hippocampal CA3 Region, Immunoglobulin Isotypes, Intracellular Signaling Peptides and Proteins, Knockout Mice, Monoclonal Antibodies, Nerve Tissue Proteins, Neurons, Synaptic Transmission, Animals, Mice, Rats
Source:Annals of Neurology
Page Range:405-418
Date:March 2020
Official Publication:https://doi.org/10.1002/ana.25666
PubMed:View item in PubMed

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