The inhibitory FcγIIb receptor dampens TLR4-mediated immune responses and is selectively up-regulated on dendritic cells from rheumatoid arthritis patients with quiescent disease

Mark H. Wenink, Kim C.M. Santegoets, Mieke F. Roelofs, Richard Huijbens, Hans J.P.M. Koenen, Ronald Van Beek, Irma Joosten, Friederike Meyer-Wentrup, Linda Mathsson, Johan Ronnelid, Gosse J. Adema, Ezio Bonvini, Scott Koenig, Wim B. Van Den Berg, Piet L.C.M. Van Riel, Timothy R.D.J. Radstake

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54 Citations (Scopus)

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcγRs and TLRs is accepted, their precise involvement remains to be elucidated. FcγRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcγRIIb 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 FcγRIIb 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 FcγRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcγRIIb 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 FcγRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcγRIIb in the induction of these phenomena. This TLR4-FcγRIIb interaction was shown to dependent on the PI3K and Akt pathway.

Original languageEnglish
Pages (from-to)4509-4520
Number of pages12
JournalJournal of Immunology
Volume183
Issue number7
DOIs
Publication statusPublished - 1 Oct 2009
Externally publishedYes

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