Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy
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| Názov: | Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy |
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| Autori: | Bernard-Valnet, Raphaël, Frieser, David, Nguyen, Xuan-Hung, Khajavi, Leila, Quériault, Clémence, Arthaud, Sébastien, Melzi, Silvia, Fusade-Boyer, Maxime, Masson, Frederick, Zytnicki, Matthias, Saoudi, Abdelhadi, Dauvilliers, Yves, Peyron, Christelle, Bauer, Jan, Liblau, Roland |
| Prispievatelia: | Pistre, Karine, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service of Neurology CHUV, Lausanne, Switzerland, Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital Lausanne (CHUV), Vinmec Healthcare System (VINMEC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôtes-agents pathogènes Toulouse (IHAP), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département de Neurologie Hôpital Gui de Chauliac - CHU Montpellier, Hôpital Gui de Chauliac CHU Montpellier, Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier)-Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Center for Brain Research Vienna, Austria, Medizinische Universität Wien = Medical University of Vienna, Département Immunologie CHU Toulouse, Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie CHU Toulouse, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Pandemrix (R) is a trademark of the GSK group of companies. This work was supported by Inserm, CNRS, and grants from Agence Nationale pour la Recherche (CE14-0016, CE17-0014), Toulouse University, Fondation Bettencourt-Schueller (Emergence Idex), ERA-Net Narcomics and GlaxoSmithKline., ANR-18-CE17-0014,NARCO-T1,Physiopathologie de la narcolepsie de type 1(2018), ANR-14-CE14-0016,ImmunitySleep,Mécanismes auto-immuns dans la narcolepsie avec cataplexie(2014) |
| Zdroj: | Brain. 145:2018-2030 |
| Informácie o vydavateľovi: | Oxford University Press (OUP), 2022. |
| Rok vydania: | 2022 |
| Predmety: | 0301 basic medicine, MESH: T-Lymphocytes / immunology, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Interferon-gamma, MESH: Orexins, [SDV]Life Sciences [q-bio], T-Lymphocytes, MESH: Neurons, T cells, narcolepsy, Autoimmunity, Autoantigens, MESH: Influenza Vaccines / adverse effects, orexinergic neurons, Interferon-gamma, Mice, 03 medical and health sciences, MESH: Autoimmunity, MESH: Narcolepsy / chemically induced, MESH: Inflammation / complications, Animals, MESH: Animals, MESH: Vaccination / adverse effects, MESH: Mice, Narcolepsy, Inflammation, Neurons, Orexins, 0303 health sciences, autoimmunity, Vaccination, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Hemagglutinins, Hemagglutinins, MESH: Autoantigens, Influenza Vaccines, [SDV.IMM]Life Sciences [q-bio]/Immunology, interferon-gamma |
| Popis: | Narcolepsy with cataplexy or narcolepsy type 1 is a disabling chronic sleep disorder resulting from the destruction of orexinergic neurons in the hypothalamus. The tight association of narcolepsy with HLA-DQB1*06:02 strongly suggest an autoimmune origin to this disease. Furthermore, converging epidemiological studies have identified an increased incidence for narcolepsy in Europe following Pandemrix® vaccination against the 2009–2010 pandemic ‘influenza’ virus strain. The potential immunological link between the Pandemrix® vaccination and narcolepsy remains, however, unknown. Deciphering these mechanisms may reveal pathways potentially at play in most cases of narcolepsy. Here, we developed a mouse model allowing to track and study the T-cell response against ‘influenza’ virus haemagglutinin, which was selectively expressed in the orexinergic neurons as a new self-antigen. Pandemrix® vaccination in this mouse model resulted in hypothalamic inflammation and selective destruction of orexin-producing neurons. Further investigations on the relative contribution of T-cell subsets in this process revealed that haemagglutinin-specific CD4 T cells were necessary for the development of hypothalamic inflammation, but insufficient for killing orexinergic neurons. Conversely, haemagglutinin-specific CD8 T cells could not initiate inflammation but were the effectors of the destruction of orexinergic neurons. Additional studies revealed pathways potentially involved in the disease process. Notably, the interferon-γ pathway was proven essential, as interferon-γ-deficient CD8 T cells were unable to elicit the loss of orexinergic neurons. Our work demonstrates that an immunopathological process mimicking narcolepsy can be elicited by immune cross-reactivity between a vaccine antigen and a neuronal self-antigen. This process relies on a synergy between autoreactive CD4 and CD8 T cells for disease development. This work furthers our understanding of the mechanisms and pathways potentially involved in the development of a neurological side effect due to a vaccine and, likely, to narcolepsy in general. |
| Druh dokumentu: | Article |
| Jazyk: | English |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awab455 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/35552381 https://ut3-toulouseinp.hal.science/hal-03669984v1 https://doi.org/10.1093/brain/awab455 |
| Rights: | OUP Standard Publication Reuse |
| Prístupové číslo: | edsair.doi.dedup.....256082ebc2f5adfcbe907d0baf8d950a |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Narcolepsy with cataplexy or narcolepsy type 1 is a disabling chronic sleep disorder resulting from the destruction of orexinergic neurons in the hypothalamus. The tight association of narcolepsy with HLA-DQB1*06:02 strongly suggest an autoimmune origin to this disease. Furthermore, converging epidemiological studies have identified an increased incidence for narcolepsy in Europe following Pandemrix® vaccination against the 2009–2010 pandemic ‘influenza’ virus strain. The potential immunological link between the Pandemrix® vaccination and narcolepsy remains, however, unknown. Deciphering these mechanisms may reveal pathways potentially at play in most cases of narcolepsy. Here, we developed a mouse model allowing to track and study the T-cell response against ‘influenza’ virus haemagglutinin, which was selectively expressed in the orexinergic neurons as a new self-antigen. Pandemrix® vaccination in this mouse model resulted in hypothalamic inflammation and selective destruction of orexin-producing neurons. Further investigations on the relative contribution of T-cell subsets in this process revealed that haemagglutinin-specific CD4 T cells were necessary for the development of hypothalamic inflammation, but insufficient for killing orexinergic neurons. Conversely, haemagglutinin-specific CD8 T cells could not initiate inflammation but were the effectors of the destruction of orexinergic neurons. Additional studies revealed pathways potentially involved in the disease process. Notably, the interferon-γ pathway was proven essential, as interferon-γ-deficient CD8 T cells were unable to elicit the loss of orexinergic neurons. Our work demonstrates that an immunopathological process mimicking narcolepsy can be elicited by immune cross-reactivity between a vaccine antigen and a neuronal self-antigen. This process relies on a synergy between autoreactive CD4 and CD8 T cells for disease development. This work furthers our understanding of the mechanisms and pathways potentially involved in the development of a neurological side effect due to a vaccine and, likely, to narcolepsy in general. |
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| ISSN: | 14602156 00068950 |
| DOI: | 10.1093/brain/awab455 |