title: A shift in the balance of inhibitory and activating Fcgamma receptors on monocytes toward the inhibitory Fcgamma receptor IIb is associated with prevention of monocyte activation in rheumatoid arthritis.
abstract: OBJECTIVE
  To assess surface expression of the inhibitory receptor for IgG (Fcgamma receptor IIb [FcgammaRIIb]) in relation to activating FcgammaR on monocyte/macrophages from patients with rheumatoid arthritis (RA) and healthy controls and to study the influence of proinflammatory and antiinflammatory cytokines on the balance of inhibitory and activating FcgammaR.
  
  
  METHODS
  Using a combination of genotyping and phenotyping, surface expression of FcgammaRIIb on monocytes from healthy control subjects and RA patients was demonstrated. Expression of FcgammaR on CD14+ monocytes was assessed by flow cytometry. Regulation of inhibitory and activating FcgammaR on monocytes by proinflammatory (interferon-gamma [IFNgamma], tumor necrosis factor alpha [TNFalpha]) and antiinflammatory (interleukin-4 [IL-4], IL-10) cytokines was studied. A functional change in cytokine-modulated monocytes was assessed in secondary cultures by their ability to produce TNFalpha upon FcgammaR crosslinking by IgG.
  
  
  RESULTS
  Monocytes from healthy controls and RA patients expressed FcgammaRIIb at similar levels, in contrast to the higher levels of activating FcgammaRI and FcgammaRIIa in RA patients. The regulation of FcgammaR expression was comparable for patients and controls. IFNgamma selectively up-regulated FcgammaRI. TNFalpha down-regulated expression of FcgammaRIIb and the activating FcgammaR, whereas IL-10 up-regulated expression of monocytic FcgammaRIIb and all activating FcgammaR. Increased or sustained levels of activating over inhibitory FcgammaR induced by IFNgamma, TNFalpha, and IL-10 alone were associated with enhanced IgG-triggered TNFalpha production. In contrast, IL-4 and, more specifically, IL-4 plus IL-10 altered the FcgammaR balance in favor of FcgammaRIIb and completely prevented IgG-triggered TNFalpha production.
  
  
  CONCLUSIONS
  The altered balance of FcgammaR in favor of activating receptors in RA may contribute to increased activation of monocyte/macrophages. A change in the FcgammaR balance toward the inhibitory FcgammaRIIb may offer a novel treatment strategy for preventing the pleiotropic activity of FcgammaR-triggered macrophages.
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Siska
authors.initials: S
authors.lastname: Wijngaarden
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Kim M G
authors.initials: KM
authors.lastname: Jacobs
authors.forename: Johannes W J
authors.initials: JW
authors.lastname: Bijlsma
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.forename: Joel A G
authors.initials: JA
authors.lastname: van Roon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D004338:Drug Combinations; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D003432:Cross-Linking Reagents; D016207:Cytokines; D004338:Drug Combinations; C080571:Fc gamma receptor IIB; D007074:Immunoglobulin G; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha