TY - JOUR T1 - On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis DO - 10.1136/annrheumdis-2019-215698 SP - annrheumdis-2019-215698 AU - Theresa Kissel AU - Karin Anna van Schie AU - Lise Hafkenscheid AU - Anders Lundquist AU - Heidi Kokkonen AU - Manfred Wuhrer AU - Tom WJ Huizinga AU - Hans Ulrich Scherer AU - René Toes AU - Solbritt Rantapää-Dahlqvist Y1 - 2019/08/30 UR - http://ard.bmj.com/content/early/2019/09/09/annrheumdis-2019-215698.abstract N2 - 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. ER -