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

A Vuorela,K Leskinen,T Härkönen,A Vaheri,O Vaarala,H Pessa,P Saavalainen,M Knip,O Saarenpää-Heikkilä,P Olsen,S Meri,T Kirjavainen,M Partinen,J Ilonen,I Stracenski,T L Freitag

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.

Highlights

Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with human leukocyte antigen (HLA)-DQB1*0602, thereby suggesting an immunological origin
We hypothesized that CD4+ Tcells primed by influenza A (H1N1) virus peptides cross-react with CNS autoantigens, and orchestrate an immune-mediated attack on the hypocretin neuronal network in NT1
HLA class II-associated autoimmune diseases are considered antigen driven, tissue pathology is not mediated by CD4+ T-cells only

Summary

Introduction

Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents These results identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1. We previously reported that Pandemrix-associated NT1 patients showed enhanced antibody responses to influenza A virus proteins present in Pandemrix vaccine[16]. This suggested that vaccinees who later developed NT1 may have mounted aberrant T-cell responses to Pandemrix. Vaccinees have increased antibody levels against human POMT1, suggesting that Pandemrix vaccination triggers POMT1 autoimmunity These findings provide a link between influenza A (H1N1) virus-directed T-cell immunity and the development of autoimmunity in NT1

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Results

Conclusion