Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1
Arja Vuorela, Tobias Freitag, Katarzyna Leskinen, Heli K. J. Pessa, Taina Härkönen, I. Stracenski, Turkka Kirjavainen, Päivi Olsén, Outi Saarenpää‐Heikkilä, Jorma Ilonen, Mikael Knip, Antti Vaheri, Markku Partinen, Päivi Saavalainen, Seppo Meri, Outi Vaarala
Abstract
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 (NA 175–189 ) and nucleoprotein 214–228 (NP 214–228 ), but also respond to a NA 175–189 -mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1 675–689 ). 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 NA 175–189 or POMT1 675–689 . 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.