Narcolepsy as an immune-mediated disease

Abstract

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. This disease is secondary to the specific loss of hypothalamic hypocretin (orexin)-producing neurons in the lateral hypothalamus. An autoimmune basis for the disease has long been suspected based on its strong association with the genetic marker DQB1∗06:02, and current studies greatly support this hypothesis. Narcolepsy with hypocretin deficiency is associated with human leukocyte antigen (HLA) and T cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a peptide unique to hypocretin-producing neurons via specific HLA-peptide-TCR interactions. This concept has gained a lot of notoriety after the increase of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Scandinavia. The surge of narcolepsy cases subsequent to influenza A H1N1 infection and H1N1 vaccination suggests that processes such as molecular mimicry or bystander activation might be crucial for disease development.

Figure 1

(a) Molecular mimicry describes the activation of cross-reactive TH1 cells that recognize both the microbial epitope [I] and the autoantigen [II]. Activation of the cross-reactive T cells results in the release of cytokines and chemokines [III] that recruit and activate monocytes and macrophages, which mediate self-tissue damage. The subsequent release of self-tissue antigens and their uptake by APCs perpetuates the autoimmune disease [IV]. (b) Molecular mimicry at the MHC/TCR synapses level. Molecular mimicry between infectious agents (H1N1 and/or streptococcus pyogenes) and hypocretin neuron autoantigens. Sequence and structural homology between foreign [I] and self-peptides [II] are required for molecular mimicry to occur. 
The MHC binding groove selects the peptide fragment with a specific amino acid sequence in the context of DQA1∗01:02-DQB1∗06:02. The TCR recognizes a presented peptide with a specific amino acid sequence [I and II].
 Activated CD4⁺ T cells cross-react and recognize hypocretin neuron autoantigens as foreign molecules, prompting an autoimmune response against hypocretin neurons [II].