title: FcγRIIIa expression on monocytes in rheumatoid arthritis: role in immune-complex stimulated TNF production and non-response to methotrexate therapy.
abstract: OBJECTIVE
  The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy.
  
  
  METHODS
  FcγRIIIa/CD16 expression on CD14(low) and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined.
  
  
  RESULTS
  Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers.
  
  
  CONCLUSIONS
  Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy.
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds, United Kingdom.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Cooper
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Martin
authors.forename: James I
authors.initials: JI
authors.lastname: Robinson
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mackie
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Charles
authors.forename: Jackie
authors.initials: J
authors.lastname: Nam
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D012189:Retrospective Studies; D013256:Steroids / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: C496124:FCGR3A protein, human; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha; D008727:Methotrexate