The functional variant of the inhibitory Fcγ receptor IIb (CD32B) is associated with the rate of radiologic joint damage and dendritic cell function in rheumatoid arthritis

Objective. Fc gamma receptors (Fc gamma Rs) recognize immune complexes (ICs) and coordinate the immune response by modulating the functions of dendritic cells (DCs). The purpose of this study was to unravel the role of the inhibitory Fc gamma RIIb in rheumatoid arthritis (RA) by studying the effect of the FCGR2B 695T > C polymorphism on susceptibility to RA, severity of the disease, and DC function. Methods. Genotyping was performed in RA patients (n = 246) and healthy blood donors (n = 269). The patients' demographic data, disease severity, and disease progression were assessed over a followup of 6 years. DCs were cultured for flow cytometry to determine the expression of Fc gamma Rs. For detection of Fc gamma RIIb (CD32B), a unique anti-Fc gamma RIIb antibody (2B6-fluorescein isothiocyanate [FITC]) was used. The capacity for antigen uptake by DCs was studied by assessing the uptake of FITC-labeled ICs. Levels of cytokine production by DCs were measured during lipopolysaccharide-mediated cell activation in the presence and absence of ICs. Results. Although no role of the FCGR2B variant in RA susceptibility was demonstrated, this variant was associated with a nearly doubled rate of radiologic joint damage during the first 6 years of RA. Multiple regression analysis showed that FCGR2B was by far the strongest predictor of joint damage identified to date. DCs from patients carrying this variant failed to display the inhibitory phenotype normally observed upon IC-mediated triggering of inflammation and displayed diminished Fc gamma RII-mediated antigen uptake compared with wild-type DCs. However, the levels of Fc gamma Rs were not affected, suggesting that the FCGR2B variant alters the function rather than regulation of proteins. Conclusion. This study is the first to show that a single genetic variant, the FCGR2B 695T>C polymorphism, is a critical determinant of disease severity in RA and radically changes DC behavior. Our results underscore the key role of DCs in the progression of RA and reveal Fc gamma RIIb as an important potential therapeutic target in RA and other autoimmune conditions.