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Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
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2016 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 127Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

Background: 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 aim was to analyze the evolution of ACPA response pre-dating symptom onset, using four selected citrullinated exogenous and endogenous antigens. Methods: A 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). Results: In 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. Conclusions: Anti-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.

Place, publisher, year, edition, pages
BioMed Central, 2016. Vol. 18, article id 127
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-123978DOI: 10.1186/s13075-016-1031-0ISI: 000377976100001PubMedID: 27255888OAI: oai:DiVA.org:umu-123978DiVA, id: diva2:958315
Available from: 2016-09-06 Created: 2016-07-07 Last updated: 2018-06-07Bibliographically approved
In thesis
1. Insights into the processes preceding the onset of rheumatoid arthritis
Open this publication in new window or tab >>Insights into the processes preceding the onset of rheumatoid arthritis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by the production of anti-citrullinated protein antibodies (ACPA) in the majority of all patients and a persistent inflammation in the synovial tissue leading to joint destruction. The aetiology of RA remains to a large extent unknown but is believed to be a complex interplay between genetic, environmental and stochastic factors. Recently, several infectious agents have been shown to have the capacity to induce citrullination of both endogenous and exogenous antigens e.g., Epstein-Barr virus (EBV) and Porphyromonas gingivalis (P.gingivalis). Disease progression in patients with RA is suggested to be a longstanding process that begins several years before symptom onset of RA. This hypothesis is supported by studies showing increased antibody levels against ACPA and disease related cytokines/chemokines several years before symptom onset of RA. The presence of ACPA is highly specific for RA and is already used as an indicator of progression and prognosis of the disease. This thesis is aimed to further investigate the origin and role of ACPA and the processes preceding the development of RA. New insights into these processes are of importance in order to be able to prevent the disease onset, achieve better diagnostic methods and treatments in the future.

All of the individuals included in these papers, had attended to the Department of Rheumatology at Umeå University to receive their diagnosis of RA. The register of the patients were thereafter co-analysed with the register of the Medical Biobank of Northern Sweden. Plasma/sera samples were analysed for antibodies and receptor activator of nuclear factor kappa-B ligand (RANKL) using different ELISA techniques from individuals before symptom onset (pre-symptomatic individuals) and at disease onset (patients). Cytokines/chemokines were analysed using Meso Scale Discovery methods. Levels of marginal jawbone loss were measured using dental radiographs from premolar/molar regions. The Larsen score at disease onset was used to grade radiographs of hands and feet.

In Paper I antibodies against Epstein-Barr virus nuclear antigen (EBNA) 1 and 2 (VCP1 and VCP2) and histone 4 (H4) derived citrullinated peptides (HCP1 and HCP2) were found to predate symptom onset of RA. In Paper II, antibodies against anti-P.gingivalis (anti-CPP3 and -RgpB IgG) were significantly increased in pre-symptomatic individuals and were detectable several years before symptom onset of RA. In Paper III the concentration of RANKL was shown to be increased several years before symptom onset of RA, especially in ACPA/rheumatoid factor (RF)/anti-carbamylated (CarP) antibody positive individuals. Positivity for RANKL was found to appear later in time than both positivity for ACPA, RF and anti-CarP antibodies. The highest Larsen score at disease onset was yielded when combining positivity for RANKL and anti-CarPivantibodies. In Paper IV periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals who never smoked, compared with matched controls. RANKL positive individuals particularly those that were also ACPA positive, had a significantly greater extent of jawbone loss in comparison to those individuals who were RANKL negative.

Antibodies against citrullinated exogenous and endogenous peptides were found to be associated with the symptom onset of RA. No hierarchy among the citrullinated epitopes could be identified. RANKL levels were particular increased in ACPA-positive individuals, and RANKL positivity appeared later in time than the general ACPA response. Periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals, who never smoked.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2018. p. 62
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1954
Keywords
rheumatoid arthritis, pre-symptomatic individuals, autoantibodies, anti-citrullinated protein/peptides antibodies, Epstein-barr virus, neutrophil extracellular traps, periodontitis, Porphyromonas gingivalis, receptor activator of nuclear factor kappa-B ligand
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-146293 (URN)978-91-7601-863-7 (ISBN)
Public defence
2018-04-27, Sal D, Målpunkt T, våning 9, Norrlands Universitetsjukhus, Umeå, 13:00 (English)
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Supervisors
Available from: 2018-04-06 Created: 2018-04-04 Last updated: 2018-06-09Bibliographically approved

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Johansson, LindaBrink, MikaelÄrlestig, LisbethRantapää-Dahlqvist, Solbritt

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