| Autor: |
Kreye, Jakob, Wenke, Nina K., Chayka, Mariya, Leubner, Jonas, Murugan, Rajagopal, Maier, Nikolaus, Jurek, Betty, Ly, Lam-Thanh, Brandl, Doreen, Rost, Benjamin R., Stumpf, Alexander, Schulz, Paulina, Radbruch, Helena, Hauser, Anja E., Pache, Florence, Meisel, Andreas, Harms, Lutz, Paul, Friedemann, Dirnagl, Ulrich, Garner, Craig |
| Předmět: |
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| Zdroj: |
Brain: A Journal of Neurology; Oct2016, Vol. 139 Issue 10, p2641-2652, 12p |
| Abstrakt: |
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 theNMDARare 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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