Autoimmune clue to narcolepsy

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By Eleanor McDermid, Senior medwireNews Reporter

Researchers have identified immune cells in patients with narcolepsy that react against hypocretin (HCRT), the lack of which causes the disorder.

Reactivity was associated with the production of T-helper-cell–1 cytokines, in common with autoimmune diseases and suggesting a “basis for a new approach to diagnosis of this disease,” the researchers write in Science Translational Medicine.

Patients with narcolepsy lack HCRT because of the destruction of around 70,000 hypothalamic neurons that produce the molecule. As these appear to be the only cells lost, the researchers believe that autoimmunity to HCRT is “likely a critical contributor to disease pathophysiology, although it is possible that it is only a secondary reaction to another disease-initiating process.”

But they add: “The sequence of events through which HCRT-reactive CD4+ T cells would lead to neuronal death, however, remains obscure.”

Emmanuel Mignot (Stanford School of Medicine, Palo Alto, California, USA) and co-workers looked specifically at immune reactivity to peptides presented to CD4+ T cells by the DQ0602 heterodimer. This is encoded by the human leukocyte antigen–DQ haplotype DQA1*01:02/DQB1*06:02, which is present in about 98% of narcolepsy patients, compared with 18–25% of people without the disorder.

The team identified several HCRT peptides that bound to DQ0602. In particular, they found strong binding for two peptides covering the C-terminal ends of the two functional, secreted peptides of prepro-HCRT: HCRT-1 and HCRT-2. CD4+ T cells obtained from narcolepsy patients reacted strongly to these peptides, whereas those taken from DQ0602-positive healthy controls did not.

The immune reaction was most specific when the peptides were presented by DQ0602. Presentation by peripheral blood mononuclear cells, for example, resulted in nonspecific reactivity that reduced the clear difference between patient and control cells.

T cells from all but four of 23 narcolepsy patients reacted to the two HCRT peptides, whereas none of those from 24 age- and gender-matched controls did so. An additional four patients had a monozygotic twin without narcolepsy; again, the patients’ T cells were reactive to the HCRT peptides, whereas their twins’ were not.

Mignot and team’s work also offers an explanation for the reported increase in narcolepsy cases after a 2009 European H1N1 influenza vaccination program. Administering this vaccine to patients caused an increase in T-cell reactivity to HCRT, although their symptoms did not worsen because of the pre-existing lack of most HCRT cells. The researchers then identified pH1N1 antigens that activated HCRT-reactive T cells, in a case of molecular mimicry.

“Nevertheless, other triggers must have existed before 2009,” say Mignot et al. They note that new narcolepsy cases vary by season, suggesting that influenza itself could be a trigger.

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