Narcolepsy is (not) an autoimmune disease.

Narcolepsy type 1 (NT1) is a chronic disease characterized by excessive daytime sleepiness and cataplexy. NT1 often strikes at a young age, severely impairing quality of life, and is frequently underdiagnosed or misdiagnosed. NT1 is tightly linked to deficiency in the wake-promoting and state-stabilizing hypocretin (HCRT) neuropeptides, which are produced by a small group of hypothalamic neurons. Given its strong association with the HLA-DQB1*06:02 allele, NT1 is widely assumed to result from autoimmune destruction of HCRT neurons. However, whether autoreactive immune responses represent a cause or a consequence of the disease remains an open question, and immune-mediated pathogenic mechanisms distinct from autoimmune cell killing are being explored. The observation that genes highly expressed in the hypothalamus, including HCRT, are epigenetically altered in post-mortem brain tissue from patients with NT1 has led to an alternative model whereby immune-triggered HCRT gene silencing, rather than HCRT neuron degeneration, causes HCRT deficiency. In this Perspective, we critically appraise the autoimmune and epigenetic models and their therapeutic implications and consider whether they can be reconciled.