Narcolepsy, autoimmunity, and influenza A H1N1 vaccination

Narcolepsy is a rare neurological disorder characterized by excessive daytime sleepiness (EDS) with or without cataplexy. A main pathophysiology of narcolepsy is hypocretin deficiency in the central nervous system resulting from a selective loss of hypocretin neurons in the lateral hypothalamus. To date, the pathogenesis of hypocretin neuron loss in narcolepsy is the most commonly accepted autoimmune hypothesis which is supported by genetic risk factors for narcolepsy such as HLA‑DQB1*06:02 allele and T-cell receptor alpha polymorphisms. Other evidence supporting the immune-mediated mechanisms include the presence of anti-Tribbles homolog 2 (TRIB2) and anti-streptococcal antibodies in patients with narcolepsy, seasonal patterns of narcolepsy onset, and increased incidence of narcolepsy after the H1N1 pandemic influenza A infections and vaccinations. Among several types of vaccines, the AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline) was the only vaccine found to increase the risk of narcolepsy. However, the comprehensive results of several epidemiological studies indicate the adjuvant AS03 alone cannot cause the disease. The genetic predisposition, environmental triggers, molecular mimicry of specific H1N1 antigens, and bystander immune activation caused by the adjuvant AS03 may have combined to contribute to autoimmunity against hypocretin neurons and development of narcolepsy.