title: Induction of macrophage secretion of tumor necrosis factor alpha through Fcgamma receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen.
abstract: OBJECTIVE
  Macrophage-derived tumor necrosis factor alpha (TNFalpha) is a dominant mediator of synovitis in rheumatoid arthritis (RA). This study was undertaken to assess whether and how immune complexes (ICs) formed by the interaction of disease-specific autoantibodies to citrullinated proteins (ACPAs) with their main synovial target antigen, citrullinated fibrin, contribute to TNFalpha production by macrophages.
  
  
  METHODS
  An in vitro human model was developed in which monocyte-derived macrophages were stimulated with ACPA-containing ICs that were generated by capturing ACPAs from RA sera on immobilized citrullinated fibrinogen. Cellular activation was evaluated by TNFalpha assay in culture supernatants. Selective blockade of IC interactions with the 3 classes of Fcgamma receptors (FcgammaR) was used to assess the contribution of each receptor to macrophage activation. In addition, 2 citrullinated fibrin-derived peptides bearing major ACPA epitopes were tested for their capacity to inhibit formation of macrophage-activating ACPA-containing ICs.
  
  
  RESULTS
  ACPA-containing ICs induced a dose-dependent TNFalpha secretion by macrophages from 14 of 20 healthy donors. The macrophage response was systematically higher than that of the paired monocyte precursors. TNFalpha secretion was not reduced by blockade of FcgammaRI or FcgammaRIII, but was strongly repressed when interaction of ICs with FcgammaRII was prevented. The 2 citrullinated peptides significantly inhibited ACPA reactivity to citrullinated fibrinogen and, when tested together, almost completely abolished formation of macrophage-activating ICs, thereby diminishing the secreted TNFalpha levels.
  
  
  CONCLUSIONS
  Our model demonstrates the inflammatory potential of ACPA-containing ICs via engagement of FcgammaRIIa at the surface of macrophages, strongly supporting their pathophysiologic involvement. Continuing dissection of these molecular pathways could open the way to new therapeutic approaches in patients with RA.
authors.affiliation: Unité Mixte de Recherche 5165 CNRS-Université Toulouse III, Institut Fédératif de Recherche 30 (IFR30) Toulouse, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Clavel
authors.forename: Leonor
authors.initials: L
authors.lastname: Nogueira
authors.forename: Laetitia
authors.initials: L
authors.lastname: Laurent
authors.forename: Cristina
authors.initials: C
authors.lastname: Iobagiu
authors.forename: Christian
authors.initials: C
authors.lastname: Vincent
authors.forename: Mireille
authors.initials: M
authors.lastname: Sebbag
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
mesh_terms: D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D005719:gamma-Globulins / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D001323:Autoantibodies; C489017:FCGR1A protein, human; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D005719:gamma-Globulins; D005337:Fibrin; D005340:Fibrinogen