title: Immunological and pathological characterization of fatal rebound MS activity following natalizumab withdrawal.
abstract: Severe rebound multiple sclerosis (MS) activity is a life-threatening complication of natalizumab (NTZ) withdrawal, for which pathogenesis and treatment are still unclear. We report the immunological and pathological characterization of a case of central nervous system (CNS) inflammatory demyelination after NTZ discontinuation.
  
  
  
  To understand the pathophysiology of this neuroinflammatory condition.
  
  
  
  Antemortem blood and cerebrospinal fluid (CSF) analysis was compared with postmortem pathological studies, as well as with novel flow cytometry characterization of immune cells isolated from the CNS parenchyma.
  
  
  
  Pathological analysis of the brain revealed the presence of innumerable active inflammatory demyelinating lesions typical of immunopathological pattern II. Monocytes/macrophages and B cells were enriched in the CNS parenchyma compared to the CSF. Numerous plasma cells were present in the lesions, but CD8 T lymphocytes were predominant in the parenchyma, as opposed to CD4 in the CSF. CNS-infiltrating lymphocytes expressed high levels of adhesion molecules, granzyme B (GzB), interferon-gamma (IFN-γ), and interleukin (IL)-17.
  
  
  
  Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS inflammation.
authors.affiliation: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada/Multiple Sclerosis Clinic, Division of Neurology, CHUM-Notre-Dame Hospital, Montréal, QC, Canada/Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Larochelle
authors.affiliation: Department of Neuropathology, Faculty of Medicine, Universitätsmedizin Göttingen, Göttingen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.affiliation: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Lécuyer
authors.affiliation: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
authors.forename: Simone
authors.initials: S
authors.lastname: Terouz
authors.affiliation: Department of Microbiology and Immunology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Roger
authors.affiliation: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada/Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Arbour
authors.affiliation: Department of Neuropathology, Faculty of Medicine, Universitätsmedizin Göttingen, Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada/Multiple Sclerosis Clinic, Division of Neurology, CHUM-Notre-Dame Hospital, Montréal, QC, Canada/Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D000069442:Natalizumab / Q000627:therapeutic use*; D013375:Substance Withdrawal Syndrome / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*
chemical_list: D000069442:Natalizumab; D007371:Interferon-gamma
keywords: Multiple sclerosis; flow cytometry; histopathology; lymphocytes; natalizumab; rebound