Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1

Nat Commun. 2021 Apr 16;12(1):2283. doi: 10.1038/s41467-021-22637-8.

Abstract

Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175-189 (NA175-189) and nucleoprotein 214-228 (NP214-228), but also respond to a NA175-189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675-689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175-189 or POMT1675-689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Autoantigens / immunology
  • B-Lymphocytes / immunology
  • CD4 Antigens / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cross Reactions / immunology
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • HLA-DQ beta-Chains / immunology
  • Humans
  • Infant
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza Vaccines / adverse effects*
  • Influenza Vaccines / immunology
  • Influenza, Human / immunology
  • Influenza, Human / prevention & control*
  • Influenza, Human / virology
  • Male
  • Mannosyltransferases / immunology*
  • Mice, Transgenic
  • Narcolepsy / blood
  • Narcolepsy / chemically induced
  • Narcolepsy / immunology*
  • Neuraminidase / immunology
  • T-Lymphocytes / immunology
  • Viral Proteins / immunology
  • Young Adult

Substances

  • Autoantibodies
  • Autoantigens
  • CD4 Antigens
  • Epitopes, T-Lymphocyte
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Influenza Vaccines
  • Viral Proteins
  • pandemrix
  • Mannosyltransferases
  • protein O-mannosyltransferase
  • NA protein, influenza A virus
  • Neuraminidase

Supplementary concepts

  • Narcolepsy 1