Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy

Sleep. 2006 May;29(5):633-8. doi: 10.1093/sleep/29.5.633.


Study objectives: The impairment of hypocretin neurotransmission system is considered to play a major role in the pathophysiology of narcolepsy. It has been hypothesized that autoimmune abnormalities underlie the etiology of narcolepsy, based on the tight association with HLA-DRB1*1501/ DQB1*0602. It remains unclear if autoantibodies against hypocretin receptors (hcrtrl and hcrtr2) are involved in narcolepsy.

Design: We have developed a novel radioligand binding assay to address this question. Sera from 181 patients with narcolepsy, 10 patients with other hypersomnias, and 91 control subjects were used. Human [35S]-Hcrt, hcrtrl, and hcrtr2 were synthesized by in vitro transcription/translation system. The immune complex of autoantibody and each [35S]-protein were immunoprecipitated and quantified using a radioligand-binding assay.

Results: We detected autoantibodies against hypocretin in 3 patients, hcrtrl in 1 patient, and hcrtr2 in 5 patients with narcolepsy. Positive reactions were also found against hcrtrl in 2 and hcrtr2 in 1 control subjects. No relationships were found between these autoantibodies and HLA-DRB1*1501/DQB1*0602 haplotypes, presence of cataplexy, presence of subjective nocturnal sleep disruption, or the score on the Epworth Sleepiness Scale.

Conclusions: Although we have detected autoantibodies against the hypocretin neurotransmission system, our results do not support the hypothesis that autoantibody-mediated dysfunction in the hypocretin system underlies the pathophysiology of narcolepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / immunology*
  • DNA Primers / genetics
  • Female
  • HLA-DQ Antigens / immunology
  • HLA-DQ beta-Chains
  • HLA-DR Antigens / immunology
  • HLA-DRB1 Chains
  • Haplotypes / immunology
  • Hippocampus / cytology
  • Humans
  • Hypothalamus / cytology
  • Immunoprecipitation
  • In Vitro Techniques
  • Male
  • Membrane Glycoproteins / immunology
  • Narcolepsy / diagnosis
  • Narcolepsy / genetics*
  • Narcolepsy / physiopathology*
  • Orexin Receptors
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / immunology*
  • Receptors, Neuropeptide / genetics*
  • Receptors, Neuropeptide / immunology*


  • Autoantibodies
  • DNA Primers
  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*15:01 antigen
  • Membrane Glycoproteins
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide