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  • IgM antibodies against acetylated proteins as a possible starting point of the anti-modified protein antibody response in rheumatoid arthritis

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Letter
IgM antibodies against acetylated proteins as a possible starting point of the anti-modified protein antibody response in rheumatoid arthritis
  1. Tineke J van Wesemael1,
  2. Sanne Reijm1,
  3. Atsushi Kawakami2,
  4. Annemarie L Dorjée1,
  5. Gerrie Stoeken1,
  6. Takahiro Maeda3,
  7. Shin-ya Kawashiri4,
  8. Tom W J Huizinga1,
  9. Mami Tamai4,
  10. René E M Toes1,
  11. Diane van der Woude1
  1. 1 Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  3. 3 Departments of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  4. 4 Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
  1. Correspondence to Dr Diane van der Woude, Rheumatology, Leiden University Medical Center, Leiden 233ZA, The Netherlands; dvanderwoude{at}lumc.nl

https://doi.org/10.1136/ard-2023-224553

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    Rheumatoid arthritis (RA) is characterised by the presence of anti-modified protein antibodies (AMPA): anti-citrullinated protein antibodies (ACPA), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA). These AMPA responses are specific for RA and have consistently been found to develop years before disease onset.1 2 Most studies on AMPA in (pre-disease) RA are focused on IgG antibodies. However, IgM is the first isotype generated in (auto)antibody responses. It is unclear whether IgM autoimmunity differs between AMPA targeting different post-translational modifications (PTMs). Since this could provide relevant clues on the initiation of the AMPA response, we investigated IgM levels of ACPA, anti-CarP and AAPA in different cohorts including healthy individuals, patients with RA and patients with non-RA arthritis consisting of patients with arthritis and rheumatic diseases other than RA (detailed descriptions of the cohorts and patient characteristics are provided in the online supplemental material).

    Supplemental material

    [ard-2023-224553supp001.pdf]

    First, levels were determined in sera from the Nagasaki Island study3 (online supplemental material). High levels of ACPA-IgM and anti-CarP-IgM were found in a subgroup of the ACPA-IgG-positive healthy donors (HD), but not in ACPA-IgG-negative HD or ACPA-IgG-negative non-RA patients (figure 1A). Furthermore, high AAPA-IgM levels could be readily detected among all groups and no significant difference in AAPA-IgM levels was found between ACPA-IgG-negative and ACPA-IgG-positive HD. The same pattern was also seen in sera from the early arthritis clinic (EAC) cohort,4 showing high levels of ACPA-IgM and anti-CarP-IgM almost exclusively in patients with ACPA-IgG-positive RA, but not in HD (figure 1C and online supplemental table S4). Again, high AAPA-IgM levels were not only observed in patients with ACPA-IgG-positive RA, but also in some …

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    Footnotes

    • Handling editor Josef S Smolen

    • TJvW and SR contributed equally.

    • Correction notice This article has been corrected since it published Online First. The sentence 'The lack of reactivity to control peptides without PTMs confirmed that the AAPA-IgM signal was not due to non-specific binding.' has been corrected and the author equal contribution statement added.

    • Contributors TJvW, SR, ALD and GS performed experiments. SR and TJvW analysed data and drafted the manuscript. AK, TM, SK and MT provided samples. TWJH and REMT helped with interpretation of the results. DvdW supervised project. All authors provided critical feedback.

    • Funding The project leading to this application has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 884796 and agreement No 714312). This work has been financially supported by the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking RTCure (grant no 777357), by Target to B! (grant no LSHM18055-SGF) and by Reuma Nederland (LLP5 and NR 17-1-402). REMT is the recipient of a European Research Council (ERC) advanced grant (AdG2019-884796). DvdW is the recipient of a ZonMw Vidi grant (09150172110053). This collaboration project is financed by the PPP Allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) to stimulate public-private partnerships and co-financing by health foundations that are part of the SFG.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • 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.