title: Anti-Tribbles Pseudokinase 2 (TRIB2)-Immunization Modulates Hypocretin/Orexin Neuronal Functions.
abstract: Recent findings showed that 16%-26% of narcolepsy patients were positive for anti-tribbles pseudokinase 2 (TRIB2) antibody, and the intracerebroventricular administration of immunoglobulin-G purified from anti-TRIB2 positive narcolepsy patients caused hypocretin/orexin neuron loss. We investigated the pathophysiological role of TRIB2 antibody using TRIB2-immunized rats and hypocretin/ataxin-3 transgenic (ataxin-3) mice.
  
  
  
  Plasma, cerebrospinal fluid (CSF), and hypothalamic tissues from TRIB2-immunized rats were collected. Anti-TRIB2 titers, hypocretin contents, mRNA expressions, the cell count of hypocretin neurons, and immunoreactivity of anti-TRIB2 antibodies on hypocretin neurons were investigated. The plasma from ataxin-3 mice was also used to determine the anti-TRIB2 antibody titer changes following the loss of hypocretin neurons.
  
  
  
  TRIB2 antibody titers increased in the plasma and CSF of TRIB2-immunized rats. The hypothalamic tissue immunostained with the sera from TRIB2-immunized rats revealed positive signals in the cytoplasm of hypcretin neurons. While no changes were found regarding hypothalamic hypocretin contents or cell counts, but there were significant decreases of the hypocretin mRNA level and release into the CSF. The plasma from over 26-week-old ataxin-3 mice, at the advanced stage of hypocretin cell destruction, showed positive reactions against TRIB2 antigen, and positive plasma also reacted with murine hypothalamic hypocretin neurons.
  
  
  
  Our results suggest that the general activation of the immune system modulates the functions of hypocretin neurons. The absence of a change in hypocretin cell populations suggested that factors other than anti-TRIB2 antibody play a part in the loss of hypocretin neurons in narcolepsy. The increased anti-TRIB2 antibody after the destruction of hypocretin neurons suggest that anti-TRIB2 antibody in narcolepsy patients is the consequence rather than the inciting cause of hypocretin cell destruction.
authors.affiliation: Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.|Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Honda
authors.affiliation: Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kodama
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3 / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009290:Narcolepsy / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000276:immunology* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D000068797:Orexins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014611:Vaccination
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000067699:Ataxin-3
keywords: TRIB2; ataxin-3.; hypocretin; narcolepsy; orexin