Theresa Kissel 1 , Karin Anna van Schie 2 , Lise Hafkenscheid 2 , Anders Lundquist 3 , Heidi Kokkonen 4 , Manfred Wuhrer 5 , Tom Wj Huizinga 2 , Hans Ulrich Scherer 2 , René Toes 2 , Solbritt Rantapää-Dahlqvist 4 Show Affiliations »
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. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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 incorpora tion 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 genera tion of V-domain glycans and whether such glycans are relevant for the tra nsition 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 chromatogra phy (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile ra nge (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. N oteworthy, 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 incorpora tion 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 . © Author(s) (or their employer(s)) 2019. N o commercial re-use. See rights and permissions. Published by BMJ.
Entities: Chemical
Disease
Gene
Species
Keywords:
zzm321990N-linked variable domain (V-domain) glycans; HLA-SE effects; anti-citrullinated protein antibodies (ACPA); rheumatoid arthritis (RA); ‘Sweet’ biomarker
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Year: 2019
PMID： 31471298 DOI： 10.1136/annrheumdis-2019-215698
Source DB: PubMed Journal: Ann Rheum Dis ISSN： 0003-4967 Impact factor: 19.103