Hypocretin-specific T cells mediate autoimmune sleeping disorder narcolepsy

Narcolepsy is a sleeping disorder characterized by "excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis". In recent years several studies provided evidence suggested that etiology of narcolepsy could be autoimmune in nature. Such conclusion has become more mainstream especially following observed relationship between 2009 pandemic flu vaccine, Pandemrix (from GSK), vaccination and development of sleeping disorder in a subset of vaccine recipients. In one study, it was found that Pandemrix but not Focetria flu vaccine (they differ in only one amino acid from each other) caused anti-flu antibody production that cross-reacted with hypocretin receptor.

Now, new study in Nature went further and showed that individuals suffering from narcolepsy, but not healthy controls, harbor hypocretin-specific T cells.

Antigen-specific T cells are rare so to reveal their presence the authors first non-specifically amplify T cells from PBMCs and after considerable expansion tested on hypocretin peptide pool pulsed autologous B cells. Majority of individuals with narcolepsy showed reactivity in this assay.

Single cell analysis showed that hypocretin-specific T cells consist of several clones (up to 30 different clones).       

Interestingly, most of T cells specific for hypocretin were HLA-DR restricted, rather than HLA-DQ as earlier association studies would have predicted.

Also, notably, hypocretin-specific T cells did not reacted with autologous B cells (or monocytes) pulsed with hypocretin protein suggested that this in vitro pulsing assay could not recapitulate in vivo hypocretin protein processing pathway. 

Of note, the authors showed that hypocretin-specific T cells did not cross-react with pandemic flu peptide pool or vaccine (influvac). However, they did not use Pandemrix vaccine here so these results are not conclusive. 

In summary, this study showed that narcolepsy could indeed be a bona fide autoimmune disease. As in many other autoimmune diseases exact molecular events that initiate them are yet to be discovered.

posted by David Usharauli