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

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

doi:10.1038/s41467-021-22637-8

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

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

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

44 Sitaatiot (Scopus)

18 Lataukset (Pure)

Abstrakti

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.

Alkuperäiskieli	Englanti
Artikkeli	2283
Julkaisu	Nature Communications
Vuosikerta	12
Numero	1
DOI - pysyväislinkit	https://doi.org/10.1038/s41467-021-22637-8
Tila	Julkaistu - huhtik. 2021
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

This study was performed with funding by the Finnish Ministry of Social Affairs and Health (grants STM/1524/2011, STM/4351/2011, STM/5432/2012, to S.M.), the Academy of Finland (grant 336441 to S.M.; NARPANord consortium grants 260898 to T.L.F. and 260603 to M.P.) and Sigrid Jusélius Foundation grants 1093 to S.M. and 1433 to A.V. We thank Prof. Terhi Kilpi and Dr. Hanna Nohynek (both at the National Institute for Health and Welfare, Helsinki, Finland) for collaboration in the recruitment of the patient cohort, Anne Huutoniemi (Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland) and Sanna Mäki (Department of Virology, University of Helsinki, Helsinki, Finland) for assistance in patient sample preparation, Leena Saarinen (National Institute for Health and Welfare, Helsinki, Finland) for technical assistance with RT-qPCR, and Dr. Teemu Smura (Department of Virology, University of Helsinki, Helsinki, Finland) for assistance with TCR sequencing.

YK:n kestävän kehityksen tavoitteet

Tämä tuotos edistää seuraavia kestävän kehityksen tavoitteita:

SDG 3 – Hyvä terveys ja hyvinvointi

Julkaisufoorumi-taso

Jufo-taso 3

!!ASJC Scopus subject areas

Yleinen kemia
Yleinen biokemia, genetiikka ja molekyylibiologia
Yleinen fysiikka ja tähtitiede

Pääsy asiakirjaan

10.1038/s41467-021-22637-8Lisenssi: CC BY

s41467-021-22637-8Final published version, 3,08 MBLisenssi: CC BY

http://urn.fi/URN:NBN:fi:tuni-202105205226Lisenssi: CC BY

Siteeraa tätä

Vuorela, A., Freitag, T. L., Leskinen, K., Pessa, H., Härkönen, T., Stracenski, I., Kirjavainen, T., Olsen, P., Saarenpää-Heikkilä, O., Ilonen, J., Knip, M., Vaheri, A., Partinen, M., Saavalainen, P., Meri, S., & Vaarala, O. (2021). Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1. Nature Communications, 12(1), Artikkeli 2283. https://doi.org/10.1038/s41467-021-22637-8

@article{5f2352c101b443a097a7fac6ff61a335,

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

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{\textendash}189 (NA175{\textendash}189) and nucleoprotein 214{\textendash}228 (NP214{\textendash}228), but also respond to a NA175{\textendash}189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675{\textendash}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{\textendash}189 or POMT1675{\textendash}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.",

author = "A. Vuorela and Freitag, \{T. L.\} and K. Leskinen and H. Pessa and T. H{\"a}rk{\"o}nen and I. Stracenski and T. Kirjavainen and P. Olsen and O. Saarenp{\"a}{\"a}-Heikkil{\"a} and J. Ilonen and M. Knip and A. Vaheri and M. Partinen and P. Saavalainen and S. Meri and O. Vaarala",

note = "Funding Information: This study was performed with funding by the Finnish Ministry of Social Affairs and Health (grants STM/1524/2011, STM/4351/2011, STM/5432/2012, to S.M.), the Academy of Finland (grant 336441 to S.M.; NARPANord consortium grants 260898 to T.L.F. and 260603 to M.P.) and Sigrid Jus{\'e}lius Foundation grants 1093 to S.M. and 1433 to A.V. We thank Prof. Terhi Kilpi and Dr. Hanna Nohynek (both at the National Institute for Health and Welfare, Helsinki, Finland) for collaboration in the recruitment of the patient cohort, Anne Huutoniemi (Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland) and Sanna M{\"a}ki (Department of Virology, University of Helsinki, Helsinki, Finland) for assistance in patient sample preparation, Leena Saarinen (National Institute for Health and Welfare, Helsinki, Finland) for technical assistance with RT-qPCR, and Dr. Teemu Smura (Department of Virology, University of Helsinki, Helsinki, Finland) for assistance with TCR sequencing. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = apr,

doi = "10.1038/s41467-021-22637-8",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Vuorela, A, Freitag, TL, Leskinen, K, Pessa, H, Härkönen, T, Stracenski, I, Kirjavainen, T, Olsen, P, Saarenpää-Heikkilä, O, Ilonen, J, Knip, M, Vaheri, A, Partinen, M, Saavalainen, P, Meri, S & Vaarala, O 2021, 'Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1', Nature Communications, Vuosikerta 12, Nro 1, 2283. https://doi.org/10.1038/s41467-021-22637-8

TY - JOUR

T1 - Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1

AU - Vuorela, A.

AU - Freitag, T. L.

AU - Leskinen, K.

AU - Pessa, H.

AU - Härkönen, T.

AU - Stracenski, I.

AU - Kirjavainen, T.

AU - Olsen, P.

AU - Saarenpää-Heikkilä, O.

AU - Ilonen, J.

AU - Knip, M.

AU - Vaheri, A.

AU - Partinen, M.

AU - Saavalainen, P.

AU - Meri, S.

AU - Vaarala, O.

N1 - Funding Information: This study was performed with funding by the Finnish Ministry of Social Affairs and Health (grants STM/1524/2011, STM/4351/2011, STM/5432/2012, to S.M.), the Academy of Finland (grant 336441 to S.M.; NARPANord consortium grants 260898 to T.L.F. and 260603 to M.P.) and Sigrid Jusélius Foundation grants 1093 to S.M. and 1433 to A.V. We thank Prof. Terhi Kilpi and Dr. Hanna Nohynek (both at the National Institute for Health and Welfare, Helsinki, Finland) for collaboration in the recruitment of the patient cohort, Anne Huutoniemi (Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland) and Sanna Mäki (Department of Virology, University of Helsinki, Helsinki, Finland) for assistance in patient sample preparation, Leena Saarinen (National Institute for Health and Welfare, Helsinki, Finland) for technical assistance with RT-qPCR, and Dr. Teemu Smura (Department of Virology, University of Helsinki, Helsinki, Finland) for assistance with TCR sequencing. Publisher Copyright: © 2021, The Author(s).

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-021-22637-8

DO - 10.1038/s41467-021-22637-8

M3 - Article

C2 - 33863907

AN - SCOPUS:85104457683

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2283

ER -

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

Abstrakti

Rahoitus

YK:n kestävän kehityksen tavoitteet

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

Sormenjälki

Siteeraa tätä