Abstract
ObjectiveThe expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy.MethodsFcγRIIIa/CD16 expression on CD14low and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined.ResultsIncreased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers.ConclusionIncreased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy.
Highlights
IgG-containing immune complexes (IC), such as those containing rheumatoid factors (RFs) and cyclic citrullinated peptide (CCP) autoantibodies, are found abundantly in serum and synovial fluid of patients with rheumatoid arthritis (RA) [1,2]
There was no correlation between CD16 expression levels on CD14++ monocytes and increasing age in control subjects (p = 0.13, Fig. 2A), no significant difference when control subjects were stratified according to gender (p = 0.23, Fig. 2B)
There was no significant difference in CD16 expression on CD14++ monocytes in early RA patients stratified according to gender (p = 0.437, Fig. 4A), smoking status, the presence of autoantibodies (CCP pos vs. neg p = 0.082, RF pos vs. neg p = 0.610, Fig. 4D and Fig. 4E respectively), or the presence or absence of hand or foot erosions at presentation (p = 0.327, Fig. 4H and p = 0.70, Fig. 4I respectively)
Summary
IgG-containing immune complexes (IC), such as those containing rheumatoid factors (RFs) and cyclic citrullinated peptide (CCP) autoantibodies, are found abundantly in serum and synovial fluid of patients with rheumatoid arthritis (RA) [1,2]. ICs activate various cell types following Fcc receptor (FccR) and complement receptor binding and lead to a diverse range of effector functions. The importance of an appropriate balance between activating and inhibitory FccRs in the regulation of animal models of arthritis is well recognised [6,7]. A dominant role for FccRIIIa in IgG IC-mediated inflammatory responses and in type I, II and III hypersensitivity reactions has been highlighted in diverse animal models [8], including autoantibody-induced arthritis [9]. FccRIIIa knockout mice are protected from IC-induced arthritis [10,11] with FccRIIIamediated mechanisms, but not complement, dominating in promoting organ-specific destructive pathologies [12,13]. We have recently demonstrated that genetic variation in FCGR3A is a risk factor for the development of autoantibody-positive RA [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
