High synovial expression of the inhibitory FcγRIIb in rheumatoid arthritis

Sofia E Magnusson,Ann-Kristin Ulfgren,Sandra Kleinau,Uwe Jacob,Marianne Engström

doi:10.1186/ar2206

Abstract

Activating Fc gamma receptors (FcγRs) have been identified as having important roles in the inflammatory joint reaction in rheumatoid arthritis (RA) and murine models of arthritis. However, the role of the inhibitory FcγRIIb in the regulation of the synovial inflammation in RA is less known. Here we have investigated synovial tissue from RA patients using a novel monoclonal antibody (GB3) specific for the FcγRIIb isoform. FcγRIIb was abundantly expressed in synovia of RA patients, in sharp contrast to the absence or weak staining of FcγRIIb in synovial biopsies from healthy volunteers. In addition, the expression of FcγRI, FcγRII and FcγRIII was analyzed in synovia obtained from early and late stages of RA. Compared with healthy synovia, which expressed FcγRII, FcγRIII but not FcγRI, all activating FcγRs were expressed and significantly up-regulated in RA, regardless of disease duration. Macrophages were one of the major cell types in the RA synovium expressing FcγRIIb and the activating FcγRs. Anti-inflammatory treatment with glucocorticoids reduced FcγR expression in arthritic joints, particularly that of FcγRI. This study demonstrates for the first time that RA patients do not fail to up-regulate FcγRIIb upon synovial inflammation, but suggests that the balance between expression of the inhibitory FcγRIIb and activating FcγRs may be in favour of the latter throughout the disease course. Anti-inflammatory drugs that target activating FcγRs may represent valuable therapeutics in this disease.

Highlights

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterised by autoantibody production and immune complex (IC) formation
The IV.3 monoclonal antibody (mAb) clearly stained the U937 cells while the Raji cells were partly stained (Figure 1b), indicating that the IV.3 mAb is somewhat cross reactive with FcγRIIb, as has recently been reported [35]
These results demonstrate that the GB3 mAb is specific for FcγRIIb and that it distinguishes between FcγRIIa and FcγRIIb

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterised by autoantibody production and immune complex (IC) formation. Most autoantibodies are of the IgG isotype, which have the potential to activate Fc gamma receptors (FcγRs) on leukocytes, such as macrophages, neutrophils, dendritic cells and B cells. FcγRI is a high affinity receptor that binds monomeric IgG as well as IgG-ICs, while FcγRII and FcγRIII are low affinity receptors that predominantly bind IgG-ICs. FcγRI, FcγRIIa, FcγRIIIa and FcγRIIIb are activating receptors. The γ-chain is responsible for intracellular signalling via its immunoreceptor tyrosine based activation motif (ITAM). FcγRIIa is a single chain receptor that contains an ITAM-motif in the cytoplasmic tail. FcγRIIb is an inhibitory receptor that is structurally similar to FcγRIIa, but has an immunoreceptor tyrosine based inhibitory motif in the cytoplasmic domain.

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