In the past years multiple publications have focused on the immunological etiology of narcolepsy. Despite the extremely tight association with HLA DQB1*06:02, immune cells and mechanisms responsible for the destruction of orexin neurons remained unclear.
In a recent publication (Bernard-Valnet et al., 2016), a group of French Neuroscientists from Toulouse, Montpellier and Lyon developed a new animal model. They generated a mouse line, named Orex-HA, expressing the H1N1 influenza virus as a neo-self-antigen specifically in orexinergic neurons. HA was transferred with effector neo-self-antigen–specific T cells. CD4 Th1 cells infiltrated the hypothalamus causing local inflammation, but they did not cause destruction of orexin neurons. Autoreactive CD8 T cells caused T-cell infiltration and destroyed orexin neurons in Orex-HA mice, but not in wildtype mice. Orex-HA mice developed a narcolepsy cataplexy phenotype after having received neo-self-antigen–specific T cells.
The authors assume that the CD4 T cells play a role in preparing the development of CD8 T cell response that is finally causing the destruction of orexin neurons.
This mouse model offers two new insights: 1. further understanding of relationship between the H1N1 pandemic and narcolepsy, and 2. the step from inflammation of the hypothalamus to the destruction of orexin neurons. This model might also help to consider future immune-modulating strategies.
Bernard-Valnet R, Yshii L, Quériault C, Nguyen XH, Arthaud S, Rodrigues M et al. CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. Proc Natl Acad Sci. 2016;27;113(39):10956-61