The Inhibitory FcγIIb Receptor Dampens TLR4-Mediated Immune Responses and Is Selectively Up-regulated on Dendritic Cells from Rheumatoid Arthritis Patients with Quiescent Disease

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.

Contribution of dendritic cell/T cell interactions to triggering and maintaining autoimmunity

“…Consistently, an FcγRIIB defi ciency can lead to overwhelming infl ammation as evidenced by the increased susceptibility to EAE shown by FcγRIIB knockout mice (Kalergis and Ravetch 2002;Iruretagoyena, Riedel et al 2008). Furthermore, it has been recently shown that DCs from RA patients with inactive disease express higher levels of FcγRIIB than active RA patients and healthy controls and that they inhibit TLR4 signaling, providing a novel mechanism as to how FcγRIIB exerts a regulatory role in immune responses (Wenink, Santegoets et al 2009). …”

Antigen-Presenting Cells and their Fcγ and Toll-Like Receptors: Leading Suspects in Autoimmunity

“…Coherently, APCs from RA patients have been shown to produce more TNF upon IC triggering than healthy control APCs, which can be explained by increased expression of Fc RII and Fc RIII on these cells [92,93]. High expression of the inhibitory Fc RIIb could play an important role in controlling inflammation by inhibition of activating Fc Rs and TLR4 induced cytokine production in macrophages and DCs [5,94]. Highly increased Fc RIIb expression on monocyte-derived DCs from RA patients that have sustained low disease activity without the need of medication underscores the importance of this feedback mechanism in RA [5].…”

“…High expression of the inhibitory Fc RIIb could play an important role in controlling inflammation by inhibition of activating Fc Rs and TLR4 induced cytokine production in macrophages and DCs [5,94]. Highly increased Fc RIIb expression on monocyte-derived DCs from RA patients that have sustained low disease activity without the need of medication underscores the importance of this feedback mechanism in RA [5].…”

“…The resulting immune response upon the binding of IC thus depends on the balance between the activating and inhibitory Fc Rs. Activation of Fc RIIa on monocyte-derived DCs results in DC maturation, increased stimulation of allogeneic T *Address correspondence to this author at the Radboud University Nijmegen Medical Centre, Department of Rheumatology, The Netherlands; Tel: +31243540403; Fax: +31243610516; E-mail: m.wenink@reuma.umcn.nl cells, and enhanced secretion of inflammatory cytokines, while preferential activation of Fc RIIb keeps DCs more immature, decreases the stimulation of allogeneic T cells and favors the development of Th2 responses even in the presence of a strong stimulus like lipopolysaccharide [4,5].…”

Dendritic cells in tolerance induction for the treatment of autoimmune diseases

“…Monocytederived DC, but not monocytes, for instance, from RA patients who discontinue the use of disease-modifying antirheumatic drugs express higher levels of the anti-inflammatory FCgRIIb but equal levels of the inflammatory FcgR [29]. FcgR recognize the Fc portion of IgG antibodies and depending on the type of receptor that is engaged, Fc receptors have been shown to mediate either inflammatory or antinflammatory responses after ligation of immunocomplexes (IgG-antigen conjugates) [30].…”