Objectives Rheumatoid arthritis (RA) is a severe chronic disease characterised by inflammation of synovial tissue, which causes pain and dysfunction of joints and leads to their destruction. In RA, complement has been implicated in inflammation and joint destruction based on studies showing reduced levels of native complement components and increased levels of complement metabolites in plasma, synovial fluid and synovial tissue of RA patients. However, there is limited information on local production and activation of key factors of the complement cascade in RA synovium and their potential modulation by novel anti-cytokine therapies.
Methods Using in situ hybridization, immunohistochemistry and Western blot techniques, the presence of complement proteins C3, factor B and Sc5b-9 and of the complement receptors C3aR and C5aR were evaluated in RA and osteoarthritic (OA) synovium. In addition, C3 and factor B levels in synovial fluid were determined by ELISA. Functional assessment was performed by examination of the effects of adenovirus-based sTNF-R p55 gene transfer into RA synovial fibroblasts in the SCID mouse model.
Results Complement proteins C3 and factor B were synthesised mainly around terminal vasculature in all (6/6) RA synovial specimens whereas complement receptors C3aR and C5aR were expressed in adjacent inflammatory infiltrates. In contrast, only limited local production of these factors could be observed in OA. Different activation of the complement cascade was illustrated by more intensive degradation of factor B in RA as compared to OA synovial fluid (mean: 28 vs. 48 μg/ml). Overexpression of sTNFRp55 revealed upregulation of C5 but not C3 receptor expression in the transduced RA synovial fibroblasts indicating differential effects of anti-cytokine therapies on complement factors in RA synovium.
Conclusion We conclude that local complement production and activation may play an important role in RA synovium. Moreover, modulation or inhibition of local complement production, e.g. by biologic agents and anti-C5 antibodies, which are currently investigated in clinical trials, could be an attractive therapeutic approach for RA.
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