Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy - Université Toulouse III - Paul Sabatier - Toulouse INP Accéder directement au contenu
Article Dans Une Revue Brain - A Journal of Neurology Année : 2022

Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy

Résumé

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.

Dates et versions

hal-03669984 , version 1 (17-05-2022)

Identifiants

Citer

Raphaël Bernard-Valnet, David Frieser, Xuan-Hung Nguyen, Leila Khajavi, Clémence Quériault, et al.. Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy. Brain - A Journal of Neurology , 2022, 145 (6), pp.2018-2030. ⟨10.1093/brain/awab455⟩. ⟨hal-03669984⟩
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