title: Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 Vaccination.
abstract: Type 1 narcolepsy is caused by deficiency of hypothalamic orexin/hypocretin. An autoimmune basis is suspected, but no specific antibodies, either causative or as biomarkers, have been identified. However, the AS03 adjuvanted split virion H1N1 (H1N1-AS03) vaccine, created to protect against the 2009 Pandemic, has been implicated as a trigger of narcolepsy particularly in children. Sera and CSFs from 13 H1N1-AS03-vaccinated patients (12 children, 1 young adult) with type 1 narcolepsy were tested for autoantibodies to known neuronal antigens including the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein 2 (CASPR2), both associated with encephalopathies that include disordered sleep, to rodent brain tissue including the lateral hypothalamus, and to live hippocampal neurons in culture. When sufficient sample was available, CSF levels of melanin-concentrating hormone (MCH) were measured. Sera from 44 H1N1-ASO3-vaccinated children without narcolepsy were also examined. None of these patients' CSFs or sera was positive for NMDAR or CASPR2 antibodies or binding to neurons; 4/13 sera bound to orexin-neurons in rat brain tissue, but also to other neurons. MCH levels were a marginally raised (n = 8; p = 0.054) in orexin-deficient narcolepsy patients compared with orexin-normal children (n = 6). In the 44 H1N1-AS03-vaccinated healthy children, there was no rise in total IgG levels or in CASPR2 or NMDAR antibodies three weeks following vaccination. In conclusion, there were no narcolepsy-specific autoantibodies identified in type 1 narcolepsy sera or CSFs, and no evidence for a general increase in immune reactivity following H1N1-AS03 vaccination in the healthy children. Antibodies to other neuronal specific membrane targets, with their potential for directing use of immunotherapies, are still an important goal for future research.
authors.affiliation: Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Thebault
authors.affiliation: Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Waters
authors.affiliation: Department of Paediatrics, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; The NIHR Oxford Biomedical Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Snape
authors.affiliation: Imperial College of Medicine, University of London, London, United Kingdom.
authors.forename: Dominic
authors.initials: D
authors.lastname: Cottrell
authors.affiliation: Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.affiliation: Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Tove
authors.initials: T
authors.lastname: Hallböök
authors.affiliation: Helsinki Sleep Clinic, Finnish Narcolepsy Research Centre, Helsinki, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Huutoniemi
authors.affiliation: Helsinki Sleep Clinic, Finnish Narcolepsy Research Centre, Helsinki, Finland; Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Partinen
authors.affiliation: Department of Paediatrics, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; The NIHR Oxford Biomedical Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
mesh_terms: D000293:Adolescent; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D009290:Narcolepsy / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D009474:Neurons / Q000276:immunology*; D000068797:Orexins / Q000134:cerebrospinal fluid; D011485:Protein Binding / Q000276:immunology; D017966:Pyramidal Cells / Q000276:immunology; D051381:Rats; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D000068797:Orexins