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.
Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-100483 |
Date | January 2009 |
Creators | Mullazehi, Mohammed |
Publisher | Uppsala universitet, Institutionen för onkologi, radiologi och klinisk immunologi, Uppsala : Acta Universitatis Upsaliensis |
Source Sets | DiVA Archive at Upsalla University |
Language | English |
Detected Language | English |
Type | Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
Format | application/pdf |
Rights | info:eu-repo/semantics/openAccess |
Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 444 |
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