Catherine Larochelle1, Imke Metz2, Marc-André Lécuyer3, Simone Terouz3, Michel Roger4, Nathalie Arbour5, Wolfgang Brück2, Alexandre Prat1. 1. 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. 2. Department of Neuropathology, Faculty of Medicine, Universitätsmedizin Göttingen, Göttingen, Germany. 3. Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada. 4. Department of Microbiology and Immunology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. 5. 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.
Abstract
BACKGROUND: 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. OBJECTIVE: To understand the pathophysiology of this neuroinflammatory condition. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. OBJECTIVE: To understand the pathophysiology of this neuroinflammatory condition. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: Moritz Förster; Patrick Küry; Orhan Aktas; Clemens Warnke; Joachim Havla; Reinhard Hohlfeld; Jan Mares; Hans-Peter Hartung; David Kremer Journal: Drug Saf Date: 2019-05 Impact factor: 5.606
Authors: Valeria Ramaglia; Salma Sheikh-Mohamed; Karen Legg; Calvin Park; Olga L Rojas; Stephanie Zandee; Fred Fu; Olga Ornatsky; Eric C Swanson; David Pitt; Alexandre Prat; Trevor D McKee; Jennifer L Gommerman Journal: Elife Date: 2019-08-01 Impact factor: 8.713
Authors: Jan W Traub; Hannah L Pellkofer; Katja Grondey; Ira Seeger; Christoph Rowold; Wolfgang Brück; Leila Husseini; Silke Häusser-Kinzel; Martin S Weber Journal: J Neuroinflammation Date: 2019-11-16 Impact factor: 8.322