Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain

The loss of hypothalamic hypocretin/orexin (hcrt) producing neurons causes narcolepsy with cataplexy. An autoimmune basis for the disease has long been suspected and recent results have greatly strengthened this hypothesis. Narcolepsy with hcrt deficiency is now known to be associated with a Human Leukocyte Antigen (HLA) and T-cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a single peptide unique to hcrt-cells via specific HLA–peptide–TCR interactions. Recent data have shown a robust seasonality of disease onset in children and associations with Streptococcus Pyogenes, and influenza A H1N1-infection and H1N1-vaccination, pointing towards processes such as molecular mimicry or bystander activation as crucial for disease development. We speculate that upper airway infections may be common precipitants of a whole host of CNS autoimmune complications including narcolepsy.

► Narcolepsy with cataplexy is caused by hypocretin deficiency. ► Narcolepsy is genetically linked to important regulators of immune response. ► Streptococcal and H1N1 infections are associated with onset of narcolepsy. ► This review describes the possible autoimmune basis of narcolepsy. ► Autoimmunity against CNS targets is a rapidly growing field of interest.