Abstract
IntroductionRheumatoid arthritis (RA) is an inflammatory disease, which results in destruction of the joint. The presence of immune complexes (IC) in serum and synovial fluid of RA patients might contribute to this articular damage through different mechanisms, such as complement activation. Therefore, identification of the antigens from these IC is important to gain more insight into the pathogenesis of RA. Since RA patients have antibodies against citrullinated proteins (ACPA) in their serum and synovial fluid (SF) and since elevated levels of citrullinated proteins are detected in the joints of RA patients, citrullinated antigens are possibly present in IC from RA patients.MethodsIC from serum of healthy persons, serum of RA patients and IC from synovial fluid of RA patients and Spondyloarthropathy (SpA) patients were isolated by immunoprecipitation. Identification of the antigens was performed by SDS-PAGE, mass spectrometry and immunodetection. The presence of citrullinated proteins was evaluated by anti-modified citrulline (AMC) staining.ResultsCirculating IC in the serum of RA patients and healthy controls contain fibrinogenβ and fibronectin, both in a non-citrullinated form. Additionally, in IC isolated from RA SF, fibrinogenγ and vimentin were identified as well. More importantly, vimentin and a minor portion of fibrinogenβ were found to be citrullinated in the isolated complexes. Moreover these citrullinated antigens were only found in ACPA+ patients. No citrullinated antigens were found in IC from SF of SpA patients.ConclusionsCitrullinated fibrinogenβ and citrullinated vimentin were found in IC from SF of ACPA+ RA patients, while no citrullinated antigens were found in IC from SF of ACPA- RA patients or SpA patients or in IC from serum of RA patients or healthy volunteers. The identification of citrullinated vimentin as a prominent citrullinated antigen in IC from SF of ACPA+ RA patients strengthens the hypothesis that citrullinated vimentin plays an important role in the pathogenesis of RA.
Highlights
Rheumatoid arthritis (RA) is an inflammatory disease, which results in destruction of the joint
Citrullinated fibrinogenβ and citrullinated vimentin were found in immune complexes (IC) from synovial fluid (SF) of anti-citrullinated protein/peptide antibodies (ACPA)+ RA patients, while no citrullinated antigens were found in IC from SF of ACPA- RA patients or SpA patients or in IC from serum of RA patients or healthy volunteers
Mass spectrometric analysis revealed that the eluted IC fraction from RA SF contained mainly immunoglobulins, while almost none were detected in the flow-through fraction
Summary
Rheumatoid arthritis (RA) is an inflammatory disease, which results in destruction of the joint. Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by chronic inflammation of the peripheral joints It is a complex multifactorial pathology, in which genetic and environmental factors, like smoking, can play an important role in the onset of disease and the progression of the joint damage [1,2]. The effect of the SF IC from juvenile RA patients on healthy PBMCs was studied by Jarvis et al They found that especially the high molecular weight IC, separated by size exclusion chromatography from the other immunoglobulins and low molecular weight IC, were responsible for inducing a spectrum of pro-inflammatory cytokines, such as TNFα, IL-1β, IL6, IL8 and granulocyte-macrophage colonystimulating factor (GM-CSF) [9]. When IC from RA serum or healthy serum were used, no elevated levels in TNFα could be seen [11] These reports show the relevance of IC in the joint destruction and the pathogenesis of RA
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