PMID- 26090827
OWN - NLM
STAT- MEDLINE
DCOM- 20160413
LR  - 20240326
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 6
DP  - 2015
TI  - Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 
      Vaccination.
PG  - e0129555
LID - 10.1371/journal.pone.0129555 [doi]
LID - e0129555
AB  - 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.
FAU - Thebault, Simon
AU  - Thebault S
AD  - Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, Oxford 
      University, Oxford, United Kingdom.
FAU - Waters, Patrick
AU  - Waters P
AD  - Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, Oxford 
      University, Oxford, United Kingdom.
FAU - Snape, Matthew D
AU  - Snape MD
AD  - Department of Paediatrics, John Radcliffe Hospital, University of Oxford, Oxford, 
      United Kingdom; The NIHR Oxford Biomedical Centre, Oxford University Hospitals 
      Trust, Oxford, United Kingdom.
FAU - Cottrell, Dominic
AU  - Cottrell D
AD  - Imperial College of Medicine, University of London, London, United Kingdom.
FAU - Darin, Niklas
AU  - Darin N
AD  - Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, 
      University of Gothenburg, Gothenburg, Sweden.
FAU - Hallbook, Tove
AU  - Hallbook T
AD  - Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, 
      University of Gothenburg, Gothenburg, Sweden.
FAU - Huutoniemi, Anne
AU  - Huutoniemi A
AD  - Helsinki Sleep Clinic, Finnish Narcolepsy Research Centre, Helsinki, Finland.
FAU - Partinen, Markku
AU  - Partinen M
AD  - Helsinki Sleep Clinic, Finnish Narcolepsy Research Centre, Helsinki, Finland; 
      Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
FAU - Pollard, Andrew J
AU  - Pollard AJ
AD  - Department of Paediatrics, John Radcliffe Hospital, University of Oxford, Oxford, 
      United Kingdom; The NIHR Oxford Biomedical Centre, Oxford University Hospitals 
      Trust, Oxford, United Kingdom.
FAU - Vincent, Angela
AU  - Vincent A
AD  - Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, Oxford 
      University, Oxford, United Kingdom.
LA  - eng
GR  - 10/111/01/DH_/Department of Health/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150619
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Autoantibodies)
RN  - 0 (Autoantigens)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Influenza Vaccines)
RN  - 0 (Orexins)
SB  - IM
MH  - Adolescent
MH  - Animals
MH  - Autoantibodies/blood/*immunology
MH  - Autoantigens/immunology
MH  - Brain/immunology/metabolism/pathology
MH  - Child
MH  - Child, Preschool
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Immunoglobulin G/blood/immunology
MH  - Influenza A Virus, H1N1 Subtype/*immunology
MH  - Influenza Vaccines/*adverse effects/immunology
MH  - Male
MH  - Narcolepsy/blood/cerebrospinal fluid/*immunology
MH  - Neurons/*immunology
MH  - Orexins/cerebrospinal fluid
MH  - Protein Binding/immunology
MH  - Pyramidal Cells/immunology
MH  - Rats
MH  - Young Adult
PMC - PMC4474558
COIS- Competing Interests: ST, DC, ND, AH and TH declare no competing interests. PW is 
      a co-inventor on a patent relating to assays for the detection of antibodies to 
      LGI1, CASPR2, and Contactin2, and has received royalties. MDS has been an 
      investigator for studies sponsored by GlaxoSmithKline, Novartis Vaccines, Pfizer, 
      and Sanofi Pasteur and has participated in advisory boards for these companies; 
      all payments for such services are made to the University of Oxford Department of 
      Paediatrics. MP speaks and consults for UCB Pharma, and speaks for Leiras Takeda, 
      and Cephalon, unrelated to this research. AJP, unrelated to this research, has 
      previously received grant/research support from GlaxoSmithKline, Novartis 
      Vaccines, Pfizer, and Sanofi Pasteur. AV, related to this research, with the 
      University of Oxford holds patents and receive a proportion of royalties for 
      CASPR2 antibody assays; unrelated to this research has received grant funding 
      from GSK. This does not alter the authors' adherence to PLOS ONE policies on 
      sharing data and materials.
EDAT- 2015/06/20 06:00
MHDA- 2016/04/14 06:00
PMCR- 2015/06/19
CRDT- 2015/06/20 06:00
PHST- 2014/12/09 00:00 [received]
PHST- 2015/05/11 00:00 [accepted]
PHST- 2015/06/20 06:00 [entrez]
PHST- 2015/06/20 06:00 [pubmed]
PHST- 2016/04/14 06:00 [medline]
PHST- 2015/06/19 00:00 [pmc-release]
AID - PONE-D-14-53493 [pii]
AID - 10.1371/journal.pone.0129555 [doi]
PST - epublish
SO  - PLoS One. 2015 Jun 19;10(6):e0129555. doi: 10.1371/journal.pone.0129555. 
      eCollection 2015.