title: The functional variant of the inhibitory Fcgamma receptor IIb (CD32B) is associated with the rate of radiologic joint damage and dendritic cell function in rheumatoid arthritis.
abstract: OBJECTIVE
  Fcgamma receptors (FcgammaRs) recognize immune complexes (ICs) and coordinate the immune response by modulating the functions of dendritic cells (DCs). The purpose of this study was to unravel the role of the inhibitory FcgammaRIIb in rheumatoid arthritis (RA) by studying the effect of the FCGR2B 695T>C polymorphism on susceptibility to RA, severity of the disease, and DC function.
  
  
  METHODS
  Genotyping was performed in RA patients (n = 246) and healthy blood donors (n = 269). The patients' demographic data, disease severity, and disease progression were assessed over a followup of 6 years. DCs were cultured for flow cytometry to determine the expression of FcgammaRs. For detection of FcgammaRIIb (CD32B), a unique anti-FcgammaRIIb antibody (2B6-fluorescein isothiocyanate [FITC]) was used. The capacity for antigen uptake by DCs was studied by assessing the uptake of FITC-labeled ICs. Levels of cytokine production by DCs were measured during lipopolysaccharide-mediated cell activation in the presence and absence of ICs.
  
  
  RESULTS
  Although no role of the FCGR2B variant in RA susceptibility was demonstrated, this variant was associated with a nearly doubled rate of radiologic joint damage during the first 6 years of RA. Multiple regression analysis showed that FCGR2B was by far the strongest predictor of joint damage identified to date. DCs from patients carrying this variant failed to display the inhibitory phenotype normally observed upon IC-mediated triggering of inflammation and displayed diminished FcgammaRII-mediated antigen uptake compared with wild-type DCs. However, the levels of FcgammaRs were not affected, suggesting that the FCGR2B variant alters the function rather than regulation of proteins.
  
  
  CONCLUSIONS
  This study is the first to show that a single genetic variant, the FCGR2B 695T>C polymorphism, is a critical determinant of disease severity in RA and radically changes DC behavior. Our results underscore the key role of DCs in the progression of RA and reveal FcgammaRIIb as an important potential therapeutic target in RA and other autoimmune conditions.
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. T.Radstake@reuma.umcn.nl
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Mark H
authors.initials: MH
authors.lastname: Wenink
authors.forename: Karin C A M
authors.initials: KC
authors.lastname: Nabbe
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Paco
authors.initials: P
authors.lastname: Welsing
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonvini
authors.forename: Scott
authors.initials: S
authors.lastname: Koenig
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001175:Arthrography; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007596:Joints / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C080571:Fc gamma receptor IIB; D008070:Lipopolysaccharides; D017452:Receptors, IgG