Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 Vaccination.

Simon Thebault,Patrick Waters,Niklas Darin,Angela Vincent,Dominic Cottrell,Markku Partinen,Tove Hallböök,Matthew D Snape,Anne Huutoniemi,Andrew J Pollard

doi:10.1371/journal.pone.0129555

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.

Highlights

IntroductionNarcolepsy is a lifelong and disabling condition, first described over 130 years ago [1]
Narcolepsy is a lifelong and disabling condition, first described over 130 years ago [1]. It is characterised by dysregulation of the sleep-wake cycle with inappropriate penetration of rapid eye movement (REM) sleep, and cataplexy, a sudden loss of motor tone triggered by emotion
No disease specific antibodies were found, four of 13 narcolepsy type 1 sera bound to orexin neurons, among other neurons, on brain tissue sections, suggesting some increase in neuronal autoimmunity

Summary

Introduction

Narcolepsy is a lifelong and disabling condition, first described over 130 years ago [1]. It is characterised by dysregulation of the sleep-wake cycle with inappropriate penetration of rapid eye movement (REM) sleep, and cataplexy, a sudden loss of motor tone triggered by emotion. Type 1 narcolepsy[2] is associated with a selective loss of neurons secreting neuropeptides orexin A and B, called hypocretins 1 and 2 [3]. The disease is diagnosed from the history of severe sleepiness, in addition to the co-existence of cataplexy, and a positive multiple sleep latency test (MSLT), or very low or absent CSF orexin [4]. Antibodies to various CNS proteins, or candidate antigens, have been identified in narcolepsy using a variety of approaches, but none have yet led to development of diseasespecific antibody tests (reviewed in [11,12,13]), and immunotherapies have produced variable results (reviewed in [13])

Methods

Results

Conclusion