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Letter
Genetic predisposition (HLA-SE) is associated with ACPA-IgG variable domain glycosylation in the predisease phase of RA
  1. Theresa Kissel1,
  2. Tineke J van Wesemael1,
  3. Anders Lundquist2,
  4. Heidi Kokkonen3,
  5. Atsushi Kawakami4,
  6. Mami Tamai5,
  7. Dirkjan van Schaardenburg6,7,
  8. Manfred Wuhrer8,
  9. Tom WJ Huizinga1,
  10. Hans Ulrich Scherer1,
  11. Diane van der Woude1,
  12. Solbritt Rantapää-Dahlqvist3,
  13. René E M Toes1
  1. 1 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Department of Statistics, USBE, Umea University, Umea, Sweden
  3. 3 Department of Public Health and Clinical Medicine/Rheumatology, Umea University, Umea, Sweden
  4. 4 Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  5. 5 Department of Immunology and Rheumatology Graduate School of Biomedical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  6. 6 Department of Rheumatology, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands
  7. 7 Department of Rheumatology, Reade, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
  8. 8 Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Theresa Kissel, Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands; T.kissel{at}lumc.nl

https://doi.org/10.1136/annrheumdis-2021-220841

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    In addition to Fc glycans, IgG can carry N-linked glycans in the variable domain. The abundant presence of disialylated variable domain glycans (VDGs) is a special feature of anti-citrullinated protein antibody (ACPA)-IgG and possibly other autoantibodies. The introduction of glycosylation sites is mediated by somatic hypermutation (SHM), a T-cell dependent process.1 The high frequency of glycosylation sites does not correlate with the number of SHM, pointing towards a selective advantage of B cells expressing variable domain glycosylated ACPA.2 Previously, we observed that ACPA-IgG VDGs are already present in the phase preceding rheumatoid arthritis (RA) onset and predictive for disease development.3 In addition, we provided first evidence that the human leucocyte antigen (HLA) ‘shared epitope’ (SE) alleles, the most prominent genetic risk factor for ACPA-positive RA, are associated with the presence of VDG on ACPA-IgG predisease.4 Hence, VDG could possibly explain the contribution of HLA-SE restricted T cells in the maturation of the ACPA response. Building on these results, we now hypothesised that HLA-SE alleles may not be associated with ACPA positivity as such, but with the specific presence of variable domain glycosylated ACPA-IgG, a favourable factor for the development of this multifactorial disease.

    To substantiate our hypothesis, we expanded the set of presymptomatic individuals (n=228) and RA-patients (n=126) from Sweden and analysed two additional cohorts comprising ACPA-positive Dutch subjects with arthralgia (n=239) and ACPA-positive healthy Japanese individuals (n=58) (online supplemental table S1). We determined the presence/percentage of ACPA-IgG VDG using liquid chromatography5 and assessed associations with HLA-SE (online supplemental materials and methods). In particular, we focused on the most prominent glycan peak (GP24) found on top of the variable domain,1 which carries a bisecting N-acetylglucosamine and two terminal sialic acids (G2FBS2) (figure 1A). ACPA-IgG VDG were, with a median of 58%, already …

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    Footnotes

    • Handling editor Josef S Smolen

    • TK and TJvW contributed equally.

    • Contributors TK: study concept and design, conducting experiments, aquisition of data, analysis and interpretation of the results, drafting and revising the manuscript, final approval of the manuscript. TJvW: study concept and design, statistical data analysis and interpretation of the results, drafting and revising the manuscript, final approval of the manuscript. AL and HK: statistical data analysis and interpretation of the results, critical revision and final approval of the manuscript. AK, MT, DvS, MW, TWJH and HUS: study concept and design, interpretation of the results, critical revision and final approval of the manuscript. DvdW, SR-D and REMT: study concept and design, interpretation of the results, drafting and revising the manuscript critically, final approval of the manuscript.

    • Funding This work has been financially supported by ReumaNederland (17-1-402 and 08-1-34), the IMI funded project RTCure (777357), ZonMw TOP (91214031) and by Target to B! (LSHM18055-5GF). REMT is a recipient of a European Research Council advanced grant (AdG2019-884796). The work has been further funded by the Swedish Research Council (VR Dnr: 2018–02551), the King Gustaf V’s 80 Year Fund, the King Gustaf V’s and Queen Victoria’s Fund and the Swedish Rheumatism Association.

    • Competing interests HUS, TWJH and REMT are mentioned inventors on a patent on ACPA-IgG V-domain glycosylation.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.