Abstract
BackgroundAnti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens. The aim was to analyze the evolution of ACPA response pre-dating symptom onset, using four selected citrullinated exogenous and endogenous antigens.MethodsA cohort of 521 individuals sampled before symptoms of RA appeared and 272 population controls were identified from the Biobank of Northern Sweden; 241 samples from patients with early RA were also collected. ACPA were detected by ELISA on viral citrullinated peptides (VCP) derived from Epstein-Barr-virus nuclear antigen (EBNA)1 and EBNA2 (VCP1 and VCP2) and histone-4-derived citrullinated peptides (HCP1 and HCP2).ResultsIn pre-symptomatic individuals vs. patients with early RA, anti-VCP1 antibodies were detected in 10.4 % vs. 36.1 %, anti-VCP2 in 17.1 % vs. 52.3 %, anti-HCP1 in 10.2 % vs. 37.3 %, and anti-HCP2 in 16.3 % vs. 48.5 %, respectively. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals vs. controls (p < 0.001) and were increased approaching symptom onset. Anti-VCP and anti-HCP appeared simultaneously (median (IQR) 5.3 (6) years before symptom onset) and in combination yielded a high-risk ratio for disease development (OR = 8.0–18.9). Anti-VCP2 and anti-HCP2 antibodies were associated with HLA-DRB1*0401 in pre-symptomatic individuals. Three peptidylarginine deiminase (PAD)I3/PADI4 single nucleotide polymorphisms (SNPs) were significantly associated with anti-HCP1.ConclusionsAnti-VCP and anti-HCP antibodies pre-date symptom onset and predict disease development, but no hierarchy of citrullinated epitopes can be identified. These results suggest that no inciting citrullinated antigen so far described is common to all patients with RA. The association between PADI3/PADI4 polymorphism and anti-HCP1 antibodies suggests a novel link between deimination and production of ACPA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1031-0) contains supplementary material, which is available to authorized users.
Highlights
Anti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens
We have previously described deiminated sequences contained in Epstein-Barr virus (EBV)-derived proteins EBNA1 and EBNA2 as specific targets of ACPA, [18, 19] and that sera from patients with RA react with deiminated H4 released during NETosis [14]
Concentrations of anti-VCP1, anti-VCP2, anti-HCP1 and anti-HCP2 IgG in pre-symptomatic individuals, patients with RA and controls The concentrations of anti-VCP1, anti-VCP2, anti-HCP1 and anti-HCP2 IgG were all significantly increased in the pre-symptomatic individuals and patients with RA compared with controls (p < 0.001 for all eight analyses; cases vs. controls) (Fig. 1a–d)
Summary
Anti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens. The events that take place during the pre-clinical stage and lead to the production of high-affinity polyclonal ACPA are not yet elucidated. A current hypothesis is that inflammatory/infectious stimuli induce deimination of exogenous or endogenous antigens, leading to the expansion and differentiation of ACPA-producing B cells, an event occurring mainly in ectopic lymphoid structures (ELS) [11]. Synovial fluid neutrophils have enhanced NETosis in RA, exposing citrullinated antigens that may fuel the production of ACPA [16, 17]. These observations led to the hypothesis that aberrant NETosis is a triggering event in RA, as suggested for other autoimmune diseases. We have previously described deiminated sequences contained in EBV-derived proteins EBNA1 and EBNA2 as specific targets of ACPA, [18, 19] and that sera from patients with RA react with deiminated H4 released during NETosis [14]
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