A shift in the balance of inhibitory and activating Fcγ receptors on monocytes toward the inhibitory Fcγ receptor IIb is associated with prevention of monocyte activation in rheumatoid arthritis

Objective To assess surface expression of the inhibitory receptor for IgG (Fcγ receptor IIb [FcγRIIb]) in relation to activating FcγR on monocyte/macrophages from patients with rheumatoid arthritis (RA) and healthy controls and to study the influence of proinflammatory and antiinflammatory cytokines on the balance of inhibitory and activating FcγR. Methods Using a combination of genotyping and phenotyping, surface expression of FcγRIIb on monocytes from healthy control subjects and RA patients was demonstrated. Expression of FcγR on CD14+ monocytes was assessed by flow cytometry. Regulation of inhibitory and activating FcγR on monocytes by proinflammatory (interferon‐γ [IFNγ], tumor necrosis factor α [TNFα]) and antiinflammatory (interleukin‐4 [IL‐4], IL‐10) cytokines was studied. A functional change in cytokine‐modulated monocytes was assessed in secondary cultures by their ability to produce TNFα upon FcγR crosslinking by IgG. Results Monocytes from healthy controls and RA patients expressed FcγRIIb at similar levels, in contrast to the higher levels of activating FcγRI and FcγRIIa in RA patients. The regulation of FcγR expression was comparable for patients and controls. IFNγ selectively up‐regulated FcγRI. TNFα down‐regulated expression of FcγRIIb and the activating FcγR, whereas IL‐10 up‐regulated expression of monocytic FcγRIIb and all activating FcγR. Increased or sustained levels of activating over inhibitory FcγR induced by IFNγ, TNFα, and IL‐10 alone were associated with enhanced IgG‐triggered TNFα production. In contrast, IL‐4 and, more specifically, IL‐4 plus IL‐10 altered the FcγR balance in favor of FcγRIIb and completely prevented IgG‐triggered TNFα production. Conclusion The altered balance of FcγR in favor of activating receptors in RA may contribute to increased activation of monocyte/macrophages. A change in the FcγR balance toward the inhibitory FcγRIIb may offer a novel treatment strategy for preventing the pleiotropic activity of FcγR‐triggered macrophages.