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Anti-type II collagen-IC-induced production of IL-1β and TNF-α, stimulate production of matrix met-alloproteinases from monocytes/rheumatoid arthritis synovial fibroblast co-cultures
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. (Autoimmunity)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. (Autoimmunity)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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(English)Manuscript (Other academic)
Abstract [en]

Objective: To establish an in vitro model that might explain the association between early joint destruction and the appearance of collagen type II (CII) antibodies in early Rheumatoid Arthritis (RA) patients. This RA pannus tissue model utilizes immune complexes (IC) containing CII-antibodies as stimulus and monocytes and synovial fibroblastsas responder cells. Methods: Peripheral blood mononuclear cells (PBMC) and RA synovial fibroblasts (RASF) were stimulated with IC individually as well in co-cultures. Monocytes were depleted to define the responder cells, and TNF-α and IL-1β were neutralized to study the effect on MMP production. TNF-α, IL-1β, MMP-1, MMP-8 and MMP-13 were measured in cell culture super-natants using ELISA.Results: Anti-CII-containing IC induced production of TNF-α, IL-1β and MMP-1 in PBMC cultures, and TNF-α, IL-1β, MMP-1 and MMP-8 in PBMC/fibroblast co-cultures, in a dose-dependent manner. IC-induced MMP-1 responses were stronger and more associated with induced produc-tion of IL-1β as compared to MMP-8 responses. Baseline production of IL-1β and MMP-1 increased significantly in co-cultures as compared to indi-vidual cultures, whereas this was not the effect for TNF-α and MMP-8. Monocyte depletion decreased TNF-α, IL-1β and MMP-1 production, while the effect on MMP-8 production was variable. Cytokine neutralization re-vealed that IL-1β was a stronger inducer of MMP-1 than was TNF-α.Conclusion:Synergistic actions between RASF and PBMC result in enhanced anti-CII IC-induced production of IL-1β and MMP-1. IL-1β and MMP-1 are regu-lated in parallel as anti-CII IC-induced IL-1β supports the production of MMP-1. MMP-8 seems to be regulated by other means. Anti-CII IC-induced TNF-α seems to be inferior to IL-1β concerning MMP-1 induction. The fact that IC stimulated synovial macrophages and fibroblasts to produce MMP, which are the first enzymes to cleave the interstitial collagens may explain the anti-CII-associated joint destruction apparent in early RA.

Keyword [en]
Rheumatoid Arthritis (RA), Type II collagen (CII), Collagen antibodies (Anti-CII), Immune complexes, Cytokine, IL-1β, TNF-α, Metalloproteinases (MMP), MMP-1, MMP-8, Synovial fibroblast
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology
Identifiers
URN: urn:nbn:se:uu:diva-100451OAI: oai:DiVA.org:uu-100451DiVA: diva2:210290
Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2010-01-14
In thesis
1. Anti-Collagen Type II Autoantibodies in an Acute Phenotype of Early Rheumatoid Arthritis
Open this publication in new window or tab >>Anti-Collagen Type II Autoantibodies in an Acute Phenotype of Early Rheumatoid Arthritis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune disease with systemic inflammatory features that primarily affects small peripheral joints. Type II collagen (CII), is the most abundant collagen type in joint cartilage. Antibodies against CII (anti-CII) are found in a subpopulation of RA patients. Anti-CII can form surface-bound immune complexes (IC) in inflamed joints, which might intensify joint inflammation and destruction. In this thesis I have studied the functional effects of surface-bound anti-CII–containing IC in vitro and correlated the results to clinical parameters.

Anti-CII IC induced TNF-α, IL-1β and IL-8 production from monocytes via FcγRIIa. Anti-CII levels were dichotomously distributed in RA patients where a small outlier group (3.3%) with very high anti-CII levels showed in vitro induction of pro-inflammatory cytokines by anti-CII-containing IC. These patients also had a distinct phenotype with elevated laboratory signs of inflammation and increased radiological erosions at the time of diagnosis.

In another in vitro model, co-cultured macrophages and RA synovial fibroblasts stimulated with anti-CII IC induced the production of matrix metalloproteinases (MMP)-1 and MMP-8, enzymes responsible for the initial cleavage of CII during cartilage degradation. This was mediated via production of TNF-α and IL-1β, and especially anti-CII IC-induced IL-1β sup-ported the production of MMP-1. The presence of anti-CII antibodies in patients with early synovitis was not predictive for future RA development.

In summary, I have shown how anti-CII-containing IC may explain part of the early pathogenesis and can define a distinct clinical phenotype in RA patients with high levels of anti-CII.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 444
National Category
Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-100483 (URN)978-91-554-7486-7 (ISBN)
Public defence
2009-05-13, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjöldsv. 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-01 Last updated: 2010-05-28Bibliographically approved

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