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Rising ACPA igg variable domain glycosylation pre-disease associates with an increase in autoantibody levels and the development of rheumatoid arthritis
Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.ORCID iD: 0000-0003-1524-0851
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 249-250Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Anti-citrullinated protein antibodies (ACPA) are present in the majority of rheumatoid arthritis (RA) patients (60-70%) and play a pivotal role in disease development1. ACPA IgGs are unique in a way that they are abundantly N-glycosylated within their variable regions2. These variable domain (V-domain) glycans are found on over 90% of ACPAs present in sera from RA-patients3. To undergo N-linked glycosylation, a consensus sequence in the protein backbone is required (N-X-S/T, where X ≠ P)4. Recently, it was shown that the N-linked glycosylation sites in ACPA-IgG V-domains are introduced during somatic hypermutation and that the introduction of such sites likely conveys a selective advantage to ACPA expressing B-cells5. However, it is currently unknown, whether ACPA-expressing B-cells already introduced glycosylation-sites into their V-domains before disease onset or when ACPA-V-domain glycosylation occurs.

Objectives: Investigate the appearance of ACPA V-domain glycosylation in pre-symptomatic individuals and RA patients.

Methods In a case-control study, individuals (n=201) from the Medical Biobank, who were sampled before onset of symptoms (mean±SEM predating time; 5.8±0.3 years) (140 aCCP+ and 61 aCCP-), and after diagnosis of RA (n=99, 94 aCCP+ and 5 aCCP-) and randomly selected control samples (n=43, 3 aCCP+ and 40 aCCP-) were analyzed for their ACPA IgG V-domain glycosylation levels. ACPA IgGs were affinity purified, N-linked glycans released, and 2-AA labeled for further analysis using UHPLC6. Data calibration and integration was performed and a cut-off defined. Samples below the cut-off were determined as non-detectable and excluded from the analysis. The percentage V-domain glycosylation was calculated as described previously3. Statistical calculations were performed using SPSS.

Results: Our data indicated that ACPA IgG V-domain glycans are already present years before symptom onset, in pre-symptomatic individuals who subsequently will develop RA. Analysis of matched pairs showed a significant increase of ACPA V-domain glycosylation in RA patients compared to individuals pre-disease (p<0.001). The results showed that ACPA N-glycosylation was correlated with anti-CCP concentrations pre-disease (rs =0.504, p<0.001), while no such association can be found after RA onset. Further, V-domain glycosylation levels increase closer to symptom onset.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019. Vol. 78, p. 249-250
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-161721DOI: 10.1136/annrheumdis-2019-eular.5341ISI: 000472207100546OAI: oai:DiVA.org:umu-161721DiVA, id: diva2:1339214
Conference
Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019
Note

 Supplement: 2

Meeting Abstract: OP0333

Available from: 2019-07-26 Created: 2019-07-26 Last updated: 2019-07-26Bibliographically approved

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Lundquist, AndersKokkonen, HeidiRantapää-Dahlqvist, Solbritt

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Lundquist, AndersKokkonen, HeidiRantapää-Dahlqvist, Solbritt
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StatisticsDepartment of Public Health and Clinical MedicineEpidemiology and Public Health Sciences
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Annals of the Rheumatic Diseases
Rheumatology and Autoimmunity

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