title: Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice.
abstract: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy (a sudden weakening of posture muscle tone usually triggered by emotion) caused by the loss of orexin neurons in the hypothalamus. Autoimmune mechanisms are implicated in narcolepsy by increased frequency of specific HLA alleles and the presence of specific autoantibody (anti-Tribbles homolog 2 (TRIB2) antibodies) in the sera of patients with narcolepsy. Presently, we passively transferred narcolepsy to naïve mice by injecting intra-cerebra-ventricularly (ICV) pooled IgG positive for anti-TRIB2 antibodies. Narcolepsy-IgG-injected mice had a loss of the NeuN (neuronal marker), synaptophysin (synaptic marker) and orexin-positive neurons in the lateral hypothalamus area in narcolepsy compared to control-IgG-injected mice and these changes were associated with narcolepsy-like immobility attacks at four weeks post injection and with hyperactivity and long term memory deficits in the staircase and novel object recognition tests. Similar behavioral and cognitive deficits are observed in narcoleptic patients. This is the first report of passive transfer of experimental narcolepsy to naïve mice induced by autoantibodies and supports the autoimmune pathogenesis in narcolepsy.
authors.affiliation: Dept. Neurology and Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Affiliated to Sackler Medical School, Tel Aviv University, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Katzav
authors.forename: Maria T
authors.initials: MT
authors.lastname: Arango
authors.forename: Shaye
authors.initials: S
authors.lastname: Kivity
authors.forename: Susumu
authors.initials: S
authors.lastname: Tanaka
authors.forename: Gili
authors.initials: G
authors.lastname: Givaty
authors.forename: Nancy
authors.initials: N
authors.lastname: Agmon-Levin
authors.forename: Makoto
authors.initials: M
authors.lastname: Honda
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Anaya
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shoenfeld
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002385:Cataplexy / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000473:pathology*; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009290:Narcolepsy / Q000276:immunology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D046709:Pattern Recognition, Physiological
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human
keywords: Anti-Tribbles homolog 2 (TRIB2) antibodies; Behavioral deficits; Narcolepsy; Orexin; Passive transfer