Genetic association, seasonal infections and autoimmune basis of narcolepsy

Abstract

In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky's criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.

Fig. 1

Possible pathway for a role of H1N1 seasonal infection and Pandemrix vaccination in onset of narcolepsy: the seasonal H1N1 influenza infection or the Pandemrix vaccine could stimulate auto-reactive T-cells or B-cells targeting towards hypocretin producing neurons via several different mechanisms. (i) Molecular mimicry of T-cells, it describes the activation of cross-reactive T-cells that recognize the H1N1 epitope and then the same T-cell (or a clone) migrates to the CNS, where it recognizes a antigen specific to hypocretin producing neurons (cross-reactivity). Activation of cross-reactive T cells results in release of cytokines and chemokines that recruits and activates macrophages, which mediates self-tissue damage. The subsequent release of hypocretin self antigen and their uptake by APCs perpetuate the autoimmune disease narcolepsy. (ii) H1N1 antigens or Pandemrix vaccine may cross-link the MHC and TCR molecules independent of antigen specificity and activates the cytotoxic T cells which are auto reactive and specific towards hypocretin producing neurons. (iii) Molecular mimicry involving B-cells and antibody mediated disease could also be involved, possibly targeting TRIB2 as a cross-reactive antigen. This process requires signals from activated T-cells (T-cell help). Bystander activation of resting auto-reactive B cells (iv) and T cells (v) as a result of general immune activation independent of specific antigens. Current results in narcolepsy research point towards a T-cell mechanism. APC: Antigen presenting cell; CNS: Central nervous system; H1N1: H1N1 influenza A virus or epitopes from adjuvant vaccines; MHC: Major histocompatibility complex; TCR: T-cell receptor; TRIB2: tribbles homologue 2.