On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis. Issue 12 (30th August 2019)

• Record Type: Journal Article
• Authors: Kissel, Theresa; van Schie, Karin Anna; Hafkenscheid, Lise; Lundquist, Anders; Kokkonen, Heidi; Wuhrer, Manfred; Huizinga, Tom WJ; Scherer, Hans Ulrich; Toes, René; Rantapää-Dahlqvist, Solbritt
• Is Part Of: Annals of the rheumatic diseases. Volume 78:Issue 12(2019)
• Page Start: 1616
• Page End: 1620
• Publication Date: 2019-08-30
• Subjects: rheumatoid arthritis (RA) -- anti-citrullinated protein antibodies (ACPA) -- N-linked variable domain (V-domain) glycans -- 'Sweet' biomarker -- HLA-SE effects; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-215698
• Languages: English
• ISSNs: 0003-4967

Abstract

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.