Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2

Abstract

The sleep disorder narcolepsy is linked to the HLA-DQB1*0602 haplotype and dysregulation of the hypocretin ligand-hypocretin receptor pathway. Narcolepsy was associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic. In contrast, very few cases were reported after Focetria vaccination (a differently manufactured adjuvanted influenza pandemic vaccine). We hypothesized that differences between these vaccines (which are derived from inactivated influenza viral proteins) explain the association of narcolepsy with Pandemrix-vaccinated subjects. A mimic peptide was identified from a surface-exposed region of influenza nucleoprotein A that shared protein residues in common with a fragment of the first extracellular domain of hypocretin receptor 2. A significant proportion of sera from HLA-DQB1*0602 haplotype-positive narcoleptic Finnish patients with a history of Pandemrix vaccination (vaccine-associated narcolepsy) contained antibodies to hypocretin receptor 2 compared to sera from nonnarcoleptic individuals with either 2009 A(H1N1) pandemic influenza infection or history of Focetria vaccination. Antibodies from vaccine-associated narcolepsy sera cross-reacted with both influenza nucleoprotein and hypocretin receptor 2, which was demonstrated by competitive binding using 21-mer peptide (containing the identified nucleoprotein mimic) and 55-mer recombinant peptide (first extracellular domain of hypocretin receptor 2) on cell lines expressing human hypocretin receptor 2. Mass spectrometry indicated that relative to Pandemrix, Focetria contained 72.7% less influenza nucleoprotein. In accord, no durable antibody responses to nucleoprotein were detected in sera from Focetria-vaccinated nonnarcoleptic subjects. Thus, differences in vaccine nucleoprotein content and respective immune response may explain the narcolepsy association with Pandemrix.

Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study

“…[10][11][12] In addition, the surge of cases of narcolepsy following pandemic H1N1 infection and mass vaccination with Pandemrix (GlaxoSmithKline, Brentford, Middlesex, UK) lends further support to an autoimmune etiology, [13][14][15][16] likely due to serum antibodies to H1N1 nucleoprotein in patients with vaccine-associated narcolepsy cross-reacting with the hypocretin receptor 2 (an effect observed following Pandremix, but not Focetria [Novartis, Novartis International AG, Basel, Switzerland] vaccination). 17 However, in the absence of formal identification and detailed understanding of the mechanisms linking autoimmunity with the destruction of hypocretin neurons, no disease-modifying therapies for narcolepsy have yet been developed.…”

H1N1 infection of sleep/wake regions results in narcolepsy-like symptoms

“…The tight association between narcolepsy and HLA subtypes and other genes involved in autoimmunity (10,11) has provided the framework for most research on the connection between narcolepsy and infectious agents (12). Indeed, a recent study found that sera from HLA-DQB1*0602-positive patients with Pandemrix-associated narcolepsy contained antibodies that cross-reacted with the H1N1 nucleoprotein and the HCRT receptor 2 (13). But whether the H1N1 virus itself, without mechanisms of molecular mimicry or other means of induced autoimmunity, can infect neurons that regulate arousal state and cause functional changes akin to narcolepsy has not been addressed-until now.…”

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

“…The main graded exercise in the course on the brain and the immune system that I taught vaccines and mimics the receptor for orexin in the brain. The orexin receptor is intimately involved in sleep and feeding behavior (14). The intersection of the brain and the immune system, and the genetic control of the immune response apparently recurs in my life in research.…”

“…Fifty years later, I returned to the same subject, this time in humans, who developed a neurologic disease after influenza immunization, but only when they had certain genetic backgrounds (14).…”

“…The subject of the genetic control of the immune response to a component of influenza became a major focus of my own latest research, nearly half a century later (14).…”