tetano
Editor, Senior Moderator
Brain
. 2022 May 13;awab455.
doi: 10.1093/brain/awab455. Online ahead of print.
Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy
Raphaël Bernard-Valnet[SUP] 1 2 [/SUP], David Frieser[SUP] 1 [/SUP], Xuan-Hung Nguyen[SUP] 1 3 [/SUP], Leila Khajavi[SUP] 1 [/SUP], Clémence Quériault[SUP] 1 [/SUP], Sébastien Arthaud[SUP] 4 [/SUP], Silvia Melzi[SUP] 4 [/SUP], Maxime Fusade-Boyer[SUP] 5 [/SUP], Frederick Masson[SUP] 1 [/SUP], Matthias Zytnicki[SUP] 6 [/SUP], Abdelhadi Saoudi[SUP] 1 [/SUP], Yves Dauvilliers[SUP] 7 [/SUP], Christelle Peyron[SUP] 4 [/SUP], Jan Bauer[SUP] 8 [/SUP], Roland S Liblau[SUP] 1 9 [/SUP]
Affiliations
Abstract
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.
. 2022 May 13;awab455.
doi: 10.1093/brain/awab455. Online ahead of print.
Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy
Raphaël Bernard-Valnet[SUP] 1 2 [/SUP], David Frieser[SUP] 1 [/SUP], Xuan-Hung Nguyen[SUP] 1 3 [/SUP], Leila Khajavi[SUP] 1 [/SUP], Clémence Quériault[SUP] 1 [/SUP], Sébastien Arthaud[SUP] 4 [/SUP], Silvia Melzi[SUP] 4 [/SUP], Maxime Fusade-Boyer[SUP] 5 [/SUP], Frederick Masson[SUP] 1 [/SUP], Matthias Zytnicki[SUP] 6 [/SUP], Abdelhadi Saoudi[SUP] 1 [/SUP], Yves Dauvilliers[SUP] 7 [/SUP], Christelle Peyron[SUP] 4 [/SUP], Jan Bauer[SUP] 8 [/SUP], Roland S Liblau[SUP] 1 9 [/SUP]
Affiliations
- PMID: 35552381
- DOI: 10.1093/brain/awab455
Abstract
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.