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Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis

Item Type:Article
Title:Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis
Creators Name:Kreye, J. and Wenke, N.K. and Chayka, M. and Leubner, J. and Murugan, R. and Maier, N. and Jurek, B. and Ly, L.T. and Brandl, D. and Rost, B.R. and Stumpf, A. and Schulz, P. and Radbruch, H. and Hauser, A.E. and Pache, F. and Meisel, A. and Harms, L. and Paul, F. and Dirnagl, U. and Garner, C. and Schmitz, D. and Wardemann, H. and Prüss, H.
Abstract:Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies. Using single cell cloning of full-length immunoglobulin heavy and light chain genes, we generated a panel of recombinant monoclonal NR1 antibodies from cerebrospinal fluid memory B cells and antibody secreting cells of NMDAR encephalitis patients. Cells typically carried somatically mutated immunoglobulin genes and had undergone class-switching to immunoglobulin G, clonally expanded cells carried identical somatic hypermutation patterns. A fraction of NR1 antibodies were non-mutated, thus resembling 'naturally occurring antibodies' and indicating that tolerance induction against NMDAR was incomplete and somatic hypermutation not essential for functional antibodies. However, only a small percentage of cerebrospinal fluid-derived antibodies reacted against NR1. Instead, nearly all further antibodies bound specifically to diverse brain-expressed epitopes including neuronal surfaces, suggesting that a broad repertoire of antibody-secreting cells enrich in the central nervous system during encephalitis. Our functional data using primary hippocampal neurons indicate that human cerebrospinal fluid-derived monoclonal NR1 antibodies alone are sufficient to cause neuronal surface receptor downregulation and subsequent impairment of NMDAR-mediated currents, thus providing ultimate proof of antibody pathogenicity. The observed formation of immunological memory might be relevant for clinical relapses.
Keywords:NMDA Receptor Encephalitis, Monoclonal Auto-Antibody, Cerebrospinal Fluid, Electrophysiology, Germline Antibodies, Animals, Mice
Publisher:Oxford University Press
Page Range:2641-2652
Date:1 October 2016
Official Publication:https://doi.org/10.1093/brain/aww208
PubMed:View item in PubMed

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