Open AccessInduction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis–specific autoantibodies to citrullinated proteins complexed with fibrinogen
Author(s) -
Clavel Cyril,
Nogueira Leonor,
Laurent Laetitia,
Iobagiu Cristina,
Vincent Christian,
Sebbag Mireille,
Serre Guy
Publication year - 2008
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.23284
Subject(s) - tumor necrosis factor alpha , immunology , macrophage , autoantibody , macrophage activating factor , monocyte , secretion , receptor , chemistry , antibody , immune system , medicine , endocrinology , in vitro , lymphokine , biochemistry
Objective Macrophage‐derived tumor necrosis factor α (TNFα) 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 TNFα 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 TNFα assay in culture supernatants. Selective blockade of IC interactions with the 3 classes of Fcγ receptors (FcγR) 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 TNFα secretion by macrophages from 14 of 20 healthy donors. The macrophage response was systematically higher than that of the paired monocyte precursors. TNFα secretion was not reduced by blockade of FcγRI or FcγRIII, but was strongly repressed when interaction of ICs with FcγRII 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 TNFα levels. Conclusion Our model demonstrates the inflammatory potential of ACPA‐containing ICs via engagement of FcγRIIa 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.