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Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
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2010 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 2, 383-391 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).

METHODS: A nested case-control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system.

RESULTS: The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1beta [IL-1beta], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-gamma, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow-derived factors (IL-7, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1alpha). The levels were particularly increased in anti-cyclic citrullinated peptide antibody- and rheumatoid factor-positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell-related cytokines, while chemokines, stromal cell-derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA.

CONCLUSION: Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell-related factors); after disease onset, the involvement and activation of the immune system was more general and widespread.

Place, publisher, year, edition, pages
2010. Vol. 62, no 2, 383-391 p.
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-31561DOI: 10.1002/art.27186ISI: 000279432100014PubMedID: 20112361OAI: oai:DiVA.org:umu-31561DiVA: diva2:293334
Available from: 2010-02-11 Created: 2010-02-11 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Pathogenetic factors of importance for the development and progression of rheumatoid arthritis
Open this publication in new window or tab >>Pathogenetic factors of importance for the development and progression of rheumatoid arthritis
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation eventually leading to the destruction of cartilage and bone. The aetiopathogenesis is not completely understood, but previous studies have shown that the disease is multifactorial with genetic, environmental and hormonal factors involved. Immune cells, e.g., T- and B-cells, and macrophages, migrate into the joints, with increased expression of numerous soluble factors such as cytokines, chemokines and adhesion molecules functionally active both locally and systemically. Analyses of blood samples from the Medical Biobank in Umeå from individuals before the onset of symptoms of joint disease showed that anti-citrullinated protein/peptide antibodies (ACPA) preceded the development of disease by years and this finding has been confirmed by other studies.                                        

The aim of this thesis was to identify signs of activation of the immune system analysed as up-regulation of pro- and anti-inflammatory cytokines, sero-positivity for autoantibodies, and genetic factors identified as relevant for the development and disease progression of RA. The concentrations of 30 cytokines and chemokines were measured in blood samples from individuals before the onset of symptoms, and when diagnosed with RA, together with population-based matched controls using a multiplex system. The predictive value of different isotypes (IgG, IgA, and IgM) of ACPA and rheumatoid factor (RF) before onset of symptoms and different types of ACPA (e.g., mutated citrullinated vimentin, MCV) were analysed for disease development and progression in patients with early RA and controls from Northern Sweden. These factors were related to the genetic markers, HLA- shared epitope (SE) alleles and the 1858C/T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene.                           

In paper I, it was shown that in individuals who later developed RA (i.e., pre-patients) the levels of several cytokines and related factors that represent the adaptive immune system (Th1, Th2, and T regulatory cell related factors) were significantly elevated compared with controls, whereas, after the onset of disease the involvement of the immune system was more general and widespread. In paper II, the presence of different isotypes (IgM, IgA and IgG) of ACPA in pre-patients, patients and controls was evaluated showing that both the IgG and IgA isotype predicted the onset of RA by years with the IgG isotype having the highest predictive value. In paper III, the association of the 1858T variant of PTPN22 with RA was confirmed. Furthermore, the association was restricted to autoantibody positive disease and this variant was correlated with an earlier age for disease onset. In paper IV, anti-MCV antibodies were identified as being associated with a more severe disease course of RA, measured by disease activity score, erythrocyte sedimentation rate, and swollen joint count over time compared with anti-CCP2, anti-CCP3, and anti-CCP3.1 antibodies.                                                                                               

In conclusion, individuals who later developed RA had increased concentrations of inflammatory markers reflecting an activation of the immune system years before the clinical symptoms of the disease developed. Also, the presence of ACPA of IgG and IgA isotype prior to disease onset predicted the development of RA. The PTPN22 1858T variant was associated with sero-positive RA and anti-MCV antibodies were associated with a higher inflammatory activity compared with anti-CCP2, -CCP3 and -CCP3.1 antibodies. These findings together present a possibility to better predict the development and progression of RA.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 80 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1490
Keyword
rheumatoid arthritis, cytokines, autoantibodies, isotypes, PTPN22, HLA-SE
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-54003 (URN)978-91-7459-403-4 (ISBN)
Public defence
2012-05-03, Sal B, 9 tr, byggnad 1D, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, K2003-74XD-14705-01, K2007-52X-20307-01-3, K2008-52X-20611-01-3, K2010-52X-20307-04-3
Available from: 2012-04-12 Created: 2012-04-11 Last updated: 2012-04-12Bibliographically approved

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