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Presence of immunological markers preceding the onset of rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. (Solbritt Rantapää-Dahlqvist)ORCID iD: 0000-0001-7675-3488
2015 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Förekomst av immunologiska markörer som föregår debuten av reumatoid artrit (Swedish)
Abstract [en]

Rheumatoid arthritis (RA) is a chronic inflammatory disease with an unknown aetiology characterized by joint destruction. Both genetic and environmental factors contribute to the disease development with HLA-DRB1* alleles and smoking identified as most important. The disease is characterized by the presence of autoantibodies, originally by rheumatoid factor (RF) and more recently by anti citrullinated protein/peptide antibodies (ACPA) and antibodies against carbamylated peptides (CarP). These autoantibodies are present, not only after the onset of disease, but also prior to the onset of symptoms. The development of RA is a gradual process lasting several years before the onset of any joint symptom, but when and if there is a temporal difference in the development both between and within the different antibody systems is currently unknown. B-cells produce the antibodies, and a subset of B-cells, i.e., B-regulatory (Breg) cells, produces interleukin-10, and thus have the ability to down-regulate pro-inflammatory cytokines. Whether the Breg cells are involved in the pathogenesis of RA is, as yet, unknown.

The aim of this thesis was to increase knowledge of the pathophysiological processes in the development of RA through identification of factors involved. The analyses involved detection of autoantibodies to post-translationally modified peptides/proteins in addition to RF isotypes, cell surface markers on immune cells in asymptomatic individuals, who have an increased risk of developing RA. In a co-analysis of the registers of patients with RA attending the Department of Rheumatology, with the registers from population based screening programmes within the Biobank of Northern Sweden, blood samples collected from individuals prior to the onset of symptoms were identified, as were those from population control subjects. A cohort of pre-symptomatic individuals also donated samples at the time of receiving a diagnosis of RA. First-degree relatives (FDR) of patients with RA were also identified and included for analyses.

The levels of ten different ACPAs, i.e., (fibrinogen (Fib) α563-583(573), Fibα580-600(591), Fibβ62-81a(72), Fibβ62-81b(74), Fibβ36-52, a-enolase (CEP-1), triple helical collagen type II (citC1III), filaggrin (Fil307-324), vimentin (Vim) 2-17, and Vim60-75) were measured using the ImmunoCAP ISAC system (Phadia/ThermoFischer, Uppsala, Sweden) in blood samples from individuals before the onset of symptoms and when diagnosed with RA in comparison with those in population based controls. In a subset of samples, the levels of anti-CarP antibodies were measured using ELISA coated with anti-CarP-FCS, as well as analysis of RF of IgM, IgG and IgA isotype using the EliA assay (Phadia, Uppsala, Sweden). Breg cells were analysed both with and without stimulation ex vivo along with other cell types using flow cytometry in samples from patients with RA, their first degree relatives (FDR) and healthy controls.

In paper I it was shown that levels of ACPA were initially restricted to a few antibodies but disseminated over time to involve additional different antibodies. The levels of antibodies to CEP-1, Fibß36-52, and filaggrin were significantly increased. In paper II, anti-CarP antibodies were positive in 5-13% of the individuals negative for the various ACPA studied. The presence of anti-CarP antibodies was significantly related to radiological destruction of joints at baseline, at follow-up after 24 months and to the radiological progress between baseline and 24months. In paper III, the relationships between the frequencies of RF isotypes, the ten different ACPA, anti-CCP2 and anti-CarP antibodies before the onset of any symptoms and the presence of certain combinations of antibodies were associated with a very high risk of developing RA. In paper IV Breg cells from patients with RA are functionally impaired and FDR showed a similar pattern by responding less to stimulation ex vivo than cells from healthy controls.

In conclusion, individuals who subsequently develop RA have an increased number and amount of ACPAs, anti-CarP antibodies and RF of IgM, IgG and IgA isotype, several years before symptom onset. Most of the different antibodies analysed remain associated with disease development after adjustments for each separate antibody. In FDRs, Breg cells were functionally altered in that they produce less IL-10 and consequently contribute to a more inflammation-prone status, as in their relatives with RA. These findings contribute to information about the development of RA as well as a given individual’s risk(s) of developing RA and its progression.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2015. , 69 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1714
Keyword [en]
autoantibodies, rheumatoid arthritis, anti citrullinated protein antibodies, pre-symptomatic individual
National Category
Rheumatology and Autoimmunity
Research subject
Immunology; Medicine, rheumatology
Identifiers
URN: urn:nbn:se:umu:diva-102589ISBN: 978-91-7601-259-8 (print)OAI: oai:DiVA.org:umu-102589DiVA: diva2:808421
Public defence
2015-05-29, Sal D, Målpunkt T, vån9, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council, K2010-52X-20307-04-3Swedish Research Council, K2011-68X-20611-04-3EU, European Research CouncilThe King Gustaf V's Jubilee Foundation
Available from: 2015-05-08 Created: 2015-04-28 Last updated: 2015-05-08Bibliographically approved
List of papers
1. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis
Open this publication in new window or tab >>Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis
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2013 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 4, 899-910 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the symptom onset of rheumatoid arthritis (RA) by several years. Antibodies against 10 citrullinated autoantigen-derived peptides were analysed for reactivity before onset of symptoms. METHODS: In the Medical Biobank of Northern Sweden 409 individuals were identified, of whom 386 provided 717 samples, obtained before onset of symptoms of RA (median time 7.4 (IQR 9.3) years); 1305 population based controls were also identified. Antibodies to 10 citrullinated peptides; fibrinogen (Fib) Fibα573, Fibα591, Fibß36-52, Fibß72, Fibß74, α-enolase (CEP-1), Type II Collagen citC1(III) , filaggrin, vimentin (Vim)2-17, and Vim60-75 were analysed using a microarray system. RESULTS: The antibody fluorescence intensity of Fibß36-52, Fibß74, CEP-1, citC1(III) , and filaggrin was significantly increased in pre-disease individuals compared with controls (p<0.001). The levels of the earliest detectable antibodies (Fibα591 and Vim60-75) fluctuated over time, with only a slight increase after onset of disease. Antibodies against Fibß36-52, CEP-1 and filaggrin increased gradually reaching the highest levels of all antibodies before symptom onset. A cluster of antibodies, citC1(III) , Fibα573 and Fibß74 increased only slightly before onset of symptoms but prominently after disease onset. The odds ratio for development of RA with a combination of CEP-1 and Fibß36-52 antibodies (<3.35 years pre-dating) was 38.8 (CI95%14.5-103.5) compared with having either. CONCLUSION: Development of an immune response towards citrullinated peptides is initially restricted but expands with time to induce a more specific response with increasing levels towards onset of symptoms, particularly invoving antibodies against CEP-1, Fibß36-52 and filaggrin.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-64403 (URN)10.1002/art.37835 (DOI)23310951 (PubMedID)
Available from: 2013-01-28 Created: 2013-01-28 Last updated: 2017-12-06Bibliographically approved
2. Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage
Open this publication in new window or tab >>Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage
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2015 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, 25Article in journal (Refereed) Published
Abstract [en]

The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. Methods: A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). Results: The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P < 0.001) and also increased significantly after disease onset (P < 0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P < 0.05, all). Conclusions: The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-102243 (URN)10.1186/s13075-015-0536-2 (DOI)000351576600001 ()
Available from: 2015-04-28 Created: 2015-04-22 Last updated: 2017-12-04Bibliographically approved
3. Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides and Anti-Carbamylated Antibodies in Individuals Before the Onset of Rheumatoid Arthritis
Open this publication in new window or tab >>Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides and Anti-Carbamylated Antibodies in Individuals Before the Onset of Rheumatoid Arthritis
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2016 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, 43Article in journal (Refereed) Published
Abstract [en]

Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious. 

Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays. 

Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected >= 15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [a-enolase (CEP-1/Eno(5-21))], fibrinogen (Fib)beta(36-52), Fiba(580-600), filaggrin (CCP-1/Fil(307-324)) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development. 

Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.

Keyword
Rheumatoid arthritis, Rheumatoid factor, Anti-citrullinated peptide antibodies, Pre-symptomatic individuals, Anti-carbamylated protein antibodies, Anti-CCP2 antibodies
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-102852 (URN)10.1186/s13075-016-0940-2 (DOI)000370007700002 ()26860413 (PubMedID)
Note

Originally included in thesis in manuscript form, with the title "Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides and Anti-Carbamylated Antibodies in Individuals Before the Onset of Rheumatoid Arthritis"

Available from: 2015-05-07 Created: 2015-05-07 Last updated: 2017-12-04Bibliographically approved
4. B-regulatory cells are functionally impaired in patients with rheumatoid arthritis and in their first degree relatives
Open this publication in new window or tab >>B-regulatory cells are functionally impaired in patients with rheumatoid arthritis and in their first degree relatives
(English)Article in journal (Other academic) Submitted
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-102854 (URN)
Available from: 2015-05-07 Created: 2015-05-07 Last updated: 2016-02-04Bibliographically approved

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