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The Inhibitory FcIIb Receptor Dampens TLR4-Mediated Immune Responses and Is Selectively Up-regulated on Dendritic Cells from Rheumatoid Arthritis Patients with Quiescent Disease¹

Mark H. Wenink^2,*, 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^* and Timothy R. D. J. Radstake^*

^* Department of Rheumatology, Nijmegen Centre of Molecular Life Sciences and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Bloodtransfusion and Transplantation Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Tumor Immunology Laboratory, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands; Unit of Clinical Immunology, Uppsala University, Uppsala, Sweden; and ^¶ MacroGenics Inc., Rockville, MD

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Organization of Research (The Netherlands Organisation for Scientific Research, VENI, and VIDI Laureate to T.R.) and financing from the Stichting de Drie Lichten (to M.W.).

² Address correspondence and reprint requests to Dr. M. H. Wenink, Department of Rheumatology, Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands. E-mail address: M.Wenink{at}reuma.umcn.nl

³ Abbreviations used in this paper: RA, rheumatoid arthritis; IC, immune complex; DC, dendritic cell; DAS28, disease activity score for 28 joints; DMARD, disease-modifying antirheumatic drug; MHC II, MHC class II; Peg-IC, IC isolated by PEG precipitation from serum or synovial fluid; DMARD(+) RA, RA patients having a DAS28 <3.2 on DMARDs; DMARD(–) RA, RA patients having a DAS28 <3.2 not on DMARD therapy; DC_{low FcRIIb}, DC expressing low FcRIIb level; DC_{high FcRIIb}, DC expressing a high FcRIIb level; IVIG, intravenous Ig; HSA, human serum albumin; PKC, protein kinase C; Treg, regulatory T cell.