The inhibitory Fc gamma IIb receptor dampens TLR4-mediated immune responses and is selectively up-regulated on dendritic cells from rheumatoid arthritis patients with quiescent disease.
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.
Wenink
Mark H
MH
Department of Rheumatology, Nijmegen Centre of Molecular Life Sciences and Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands. M.Wenink@reuma.umcn.nl
Santegoets
Kim C M
KC
Roelofs
Mieke F
MF
Huijbens
Richard
R
Koenen
Hans J P M
HJ
van Beek
Ronald
R
Joosten
Irma
I
Meyer-Wentrup
Friederike
F
Mathsson
Linda
L
Ronnelid
Johan
J
Adema
Gosse J
GJ
Bonvini
Ezio
E
Koenig
Scott
S
van den Berg
Wim B
WB
van Riel
Piet L C M
PL
Radstake
Timothy R D J
TR
D000368:Aged; D000936:Antigen-Antibody Complex / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D011446:Prospective Studies; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D000936:Antigen-Antibody Complex; D016207:Cytokines; C080571:Fc gamma receptor IIB; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D017452:Receptors, IgG; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4