title: Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis.
abstract: OBJECTIVE
  Most patients with anti-NMDA receptor (NMDAR) encephalitis have intrathecal synthesis of antibodies, which cause a decrease of cell surface and synaptic NMDAR. Antibodies are immunoglobulin G (IgG)1 and IgG3 subtypes and can potentially activate complement. We examined whether complement immunoreactivity and antibody-secreting cells (plasma cells/plasmablasts) are present in the brain of these patients.
  
  
  METHODS
  Cultured rat hippocampal neurons were used in an immunocytochemical assay to test whether patients' antibodies can fix complement. Using the same reagents (antibodies to C9neo, C(5b-9), C3), complement immunoreactivity was determined in the brain of 5 patients, the teratoma of 21 patients, and appropriate control tissues. A set of markers for B (CD20), T (CD3, CD4, CD8) and antibody-secreting cells (plasma cells/plasmablasts, CD138) were used to examine the brain inflammatory infiltrates.
  
  
  RESULTS
  Patients' antibodies were able to bind complement in vitro, but deposits of complement were not detected in patients' brain. Parallel experiments with teratomas showed that in contrast to the brain, the neural tissue of the tumors contained complement. Analysis of the inflammatory infiltrates in brain samples from autopsy or biopsy performed 3-4 weeks after symptom presentation demonstrated numerous antibody-secreting cells (CD138+) in perivascular, interstitial, and Virchow-Robin spaces, and B and T cells predominantly located in perivascular regions.
  
  
  CONCLUSIONS
  Complement-mediated mechanisms do not appear to play a substantial pathogenic role in anti-NMDAR encephalitis. In contrast, there are copious infiltrates of antibody-secreting cells (plasma cells/plasmablasts) in the CNS of these patients. The demonstration of these cells provides an explanation for the intrathecal synthesis of antibodies and has implications for treatment.
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: E
authors.initials: E
authors.lastname: Martinez-Hernandez
authors.forename: J
authors.initials: J
authors.lastname: Horvath
authors.forename: Y
authors.initials: Y
authors.lastname: Shiloh-Malawsky
authors.forename: N
authors.initials: N
authors.lastname: Sangha
authors.forename: M
authors.initials: M
authors.lastname: Martinez-Lage
authors.forename: J
authors.initials: J
authors.lastname: Dalmau
mesh_terms: D000818:Animals; D000921:Antibody-Producing Cells / Q000502:physiology; D001344:Autopsy; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry / Q000502:physiology; D002478:Cells, Cultured; D003168:Complement Fixation Tests; D003165:Complement System Proteins / Q000032:analysis*; D004660:Encephalitis / Q000097:blood* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D009474:Neurons / Q000502:physiology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010950:Plasma Cells / Q000502:physiology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D053668:Syndecan-1 / Q000032:analysis; D013724:Teratoma / Q000378:metabolism / Q000473:pathology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D053668:Syndecan-1; D003165:Complement System Proteins