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High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
2007 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 66, no 4, p. 537-541Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate whether the cytokine-inducing properties of surface-bound collagen type II (Cll)-containing immune complexes (IC), which were reported earlier, have any clinical impact. Methods: Anti-CII serology was analysed in 274 patients with early rheumatoid arthritis (RA). Patients with increased levels of anti-CII were followed serially for 1-5 years with regard to anti-CII IC-induced levels of tumour necrosis factor (TNF)a, interleukin (IL)1β and IL8. Levels of antibodies and IC-induced cytokines were compared with clinical indices over 5 years of follow-up. Results: 5/100 healthy controls and 24/274 (8.8%) patients with RA exhibited increased levels (>29 arbitrary units (AU)/ ml) of anti-native Cll antibodies, a non-significant difference. 9/274 (3.3%) patients with RA and no controls comprised a discrete group with high anti-CII levels >450 AU/ml. These high anti-CII level sera were associated with induction of proinflammatory cytokines by anti-CII-containing IC formed in vitro. 8/9 patients with high baseline anti-CII levels exhibited a parallel decline in antibody levels, IC-induced cytokines, C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Anti-CII-positive patients had significantly increased levels of CRP and ESR at baseline, but not later during the follow-up. Conclusions: Anti-native Cll-positive patients with RA have a distinct clinical phenotype characterised by an early acute phase response that might be driven by anti-CII-containing IC in joint cartilage.

Place, publisher, year, edition, pages
2007. Vol. 66, no 4, p. 537-541
Keyword [en]
Immunopathology, Diseases of the osteoarticular system, Inflammatory joint disease, Autoimmune disease, Chronic, Onset time, Inflammation, Acute, Phenotype, In vitro, Immune complex, Cytokine, Antibody, Collagen type II, Rheumatoid arthritis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-25688DOI: 10.1136/ard.2006.064782ISI: 000244924700020PubMedID: 17040962OAI: oai:DiVA.org:uu-25688DiVA: diva2:53462
Available from: 2008-01-28 Created: 2008-01-28 Last updated: 2017-12-07Bibliographically approved
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. p. 74
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: 2018-01-13Bibliographically approved

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Mullazehi, MohammedMathsson, LindaRönnelid, Johan

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