Activating autoantibodies against G protein-coupled receptors in narcolepsy type 1

Narcolepsy type 1 is a rare hypersomnia of central origin, which is caused by loss of hypothalamic neurons that produce the neuropeptides hypocretin-1 and -2. Hypocretin-containing nerve terminals are found in areas known to play a central role in autonomic control and in pain signaling. Cholinergic M2 receptors are found in brain areas involved with the occurrence of hallucinations and cataplexy. In addition to classical symptoms of narcolepsy, the patients suffer frequently from autonomic dysfunction, chronic pain, and hypnagogic/hypnopompic hallucinations. We aimed to test whether narcolepsy type 1 patients have autoantibodies against autonomic β2 adrenergic receptor, M2 muscarinic receptors, or nociception receptors.

We tested the serum of ten narcolepsy type 1 patients (five female) for activating β2 adrenergic receptor autoantibodies, M2 muscarinic receptor autoantibodies, and nociception receptor autoantibodies.

Ten of ten patients were positive for muscarinic M2 receptor autoantibodies (P < 0.001), 9/10 were positive for autoantibodies against nociception receptors (P < 0.001), and 5/10 were positive for β2 adrenergic receptor autoantibodies (P < 0.001).

Narcolepsy type 1 patients harbored activating autoantibodies against M2 muscarinic receptors, nociception receptors, and β2 adrenergic receptors. M2 receptor autoantibodies may be related to the occurrence of cataplexy and, moreover, hallucinations in narcolepsy since they are found in the same brain areas that are involved with these symptoms. The occurrence of nociception receptor autoantibodies strengthens the association between narcolepsy type 1 and pain. The connection between narcolepsy type 1, autonomic complaints, and the presumed cardiovascular morbidity might be associated with the occurrence of β2 adrenergic receptor autoantibodies. On the other hand, the presence of the autoantibodies may be secondary to the destruction of the hypocretin pathways.