Increased FcγRII and III expression in synovium and on monocyte derived macrophages of RA-patients results in altered function after immune complex stimulation

Introduction

Rheumatoid arthritis (RA) is characterized by extensive deposition of immune complexes (ICs) in the synovium. These ICs can communicate with resident macrophages and inflammatory cells entering from the circulation using Fcγ Receptors (FcγRs).

Objective

To determine whether macrophages of RA patients express different levels of FcγRs and whether this difference results in altered production of inflammatory mediators after stimulation with immune complexes.

Methods

Monocytes were isolated from blood of 10 RA-patients and 10 healthy controls and cultured for 7 days with M-CSF to obtain macrophages. Using FACS analysis, the expression of FcγRI, IIandIII was determined. At day 7 cells were stimulated with heat aggregated gamma globulins (HAGG) and 24 hours thereafter cytokine production was measured. In addition, immunohisto-chemistry was performed on synovial biopsies of knee joints of 27 RA patients and 5 controls. FcγRI, II and III were detected, as well as several inflammatory mediators.

Results

Macrophages derived from PBMC of RA patients showed a significantly higher expression of FcγRII (45%) and FcγRIII (15%) compared to controls. When RA cells were stimulated with HAGG, we found higher TNFα production. Also, when matrix degrading gelatinase/collagenase was detected, a significantly higher activity of these enzymes was found in the supernatants of HAGG stimulated RA macrophages vs. controls. Underlining these findings, we found highly significant positive correlations between the expression of FcγRII and III and the degree of inflammation in the joint in RA patients, but not for FcγRI. FcγRII and III expression was higher (respectively 80% and 125%) in RA synovium compared to controls. TNFα expression in the synovium was correlated with FcγRIII expression (r = 0.51). MMP-1 expression was strongly correlated with FcγRI, IIandIII (respectively r = 0.48, 0.60 and 0.62). FcγR expressions also correlated well with other cytokines, for example, IL-18 (positively: r = 0.63) and IL-12 (negatively: r = -0.46).

Conclusion

Macrophages of RA patients express higher levels of FcγRII andIII, resulting in elevated production of TNFα, and MMP-1. In addition, differences in FcγR expression in the synovium may also lead to different cytokine patterns. These data suggest that disturbed FcγR expression plays a role in RA pathology.