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Rheumatoid arthritis
On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis
  1. Theresa Kissel1,
  2. Karin Anna van Schie1,
  3. Lise Hafkenscheid1,
  4. Anders Lundquist2,
  5. Heidi Kokkonen3,
  6. Manfred Wuhrer4,
  7. Tom WJ Huizinga1,
  8. Hans Ulrich Scherer1,
  9. René Toes1,
  10. Solbritt Rantapää-Dahlqvist3
  1. 1 Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Department of Statistics, Umeå University, Umeå, Sweden
  3. 3 Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden
  4. 4 Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Theresa Kissel, Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; T.kissel{at}lumc.nl

Abstract

Objective Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable domains (V-domains). Recently, we showed that N-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients.

Methods ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative).

Results V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG.

Conclusion Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.

  • rheumatoid arthritis (RA)
  • anti-citrullinated protein antibodies (ACPA)
  • N-linked variable domain (V-domain) glycans
  • ‘Sweet’ biomarker
  • HLA-SE effects

https://doi.org/10.1136/annrheumdis-2019-215698

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    Footnotes

    • Handling editor Prof Josef S Smolen

    • Correction notice This article has been corrected since it published Online First. An error has been corrected in the abstract.

    • 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. KAvS: study concept and design, conducting experiments, aquisition of data and interpretation of the results, critical revision and final approval of the manuscript. LH: study concept and design, methodology design, conducting experiments, aquisition of data, critical revision and final approval of the manuscript. AL: statistical analyses, interpretation of the results, critical revision and final approval of the manuscript. HK: statistical analyses, critical revision and final approval of the manuscript. MW: methodology design, critical revision and final approval of the manuscript. TWJH: interpretation of the results, critical revision and final approval of the manuscript. HUS: study concept and design, interpretation of the results, critical revision and final approval of the manuscript. RT: study concept and design, interpretation of the results, drafting and revising the manuscript critically, final approval of the manuscript. SR-D: study concept and design, statistical analyses, interpretation of the results, drafting and revising the manuscript critically, final approval of the manuscript. Department of Biobank Research at Umeå University: providing patient samples and data. Västerbotten Intervention Programme: providing patient samples and data. The Northern Sweden MONICA study: providing patient samples and data. The County Council of Västerbotten: providing patient samples and data. J.W. Drijfhout: providing the CCP2 peptides.

    • Funding This work has been financially supported by ReumaNederland (17-1-402), the IMI funded project RTCure (777357), ZonMw TOP (91214031), the Swedish Research Council (VR 2017-00650) as well as 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.

    • Patient consent for publication Not required.

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