title: IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies.
abstract: OBJECTIVE
  Anticitrullinated protein antibodies (ACPA) are specifically associated with rheumatoid arthritis (RA) and produced in inflamed synovial membranes where citrullinated fibrin, their antigenic target, is abundant. We showed that immune complexes containing IgG ACPA (ACPA-IC) induce FcγR-mediated tumour necrosis factor (TNF)-α secretion in macrophages. Since IgM rheumatoid factor (RF), an autoantibody directed to the Fc fragment of IgG, is also produced and concentrated in the rheumatoid synovial tissue, we evaluated its influence on macrophage stimulation by ACPA-IC.
  
  
  METHODS
  With monocyte-derived macrophages from more than 40 healthy individuals and different human IgM cryoglobulins with RF activity, using a previously developed human in vitro model, we evaluated the effect of the incorporation of IgM RF into ACPA-IC.
  
  
  RESULTS
  IgM RF induced an important amplification of the TNF-α secretion. This effect was not observed in monocytes and depended on an increase in the number of IgG-engaged FcγR. It extended to the secretion of interleukin (IL)-1β and IL-6, was paralleled by IL-8 secretion and was not associated with overwhelming secretion of IL-10 or IL-1Ra. Moreover, the RF-induced increased proinflammatory bioactivity of the cytokine response to ACPA-IC was confirmed by an enhanced, not entirely TNF-dependent, capacity of the secreted cytokine cocktail to prompt IL-6 secretion by RA synoviocytes.
  
  
  CONCLUSIONS
  By showing that it can greatly enhance the proinflammatory cytokine response induced in macrophages by the RA-specific ACPA-IC, these results highlight a previously undescribed, FcγR-dependent strong proinflammatory potential of IgM RF. They clarify the pathophysiological link between the presence of ACPA and IgM RF, and RA severity.
authors.affiliation: Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, INSERM Unité Mixte de Recherche 1056, Toulouse, France Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, CNRS UMR 5165, Toulouse, France Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Lætitia
authors.initials: L
authors.lastname: Laurent
authors.affiliation: Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, INSERM Unité Mixte de Recherche 1056, Toulouse, France Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, CNRS UMR 5165, Toulouse, France Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France Laboratory of Cell Biology and Cytology, Centre Hospitalier Universitaire (CHU) de Toulouse, Institut Fédératif de Biologie, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Anquetil
authors.affiliation: Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, INSERM Unité Mixte de Recherche 1056, Toulouse, France Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, CNRS UMR 5165, Toulouse, France Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France Laboratory of Cell Biology and Cytology, Centre Hospitalier Universitaire (CHU) de Toulouse, Institut Fédératif de Biologie, Toulouse, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Clavel
authors.affiliation: Immunogenomics and inflammation research unit EA 4130, University of Lyon 1, Hôpital Edouard Herriot, Lyon, France.
authors.forename: Ndiémé
authors.initials: N
authors.lastname: Ndongo-Thiam
authors.affiliation: Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, INSERM Unité Mixte de Recherche 1056, Toulouse, France Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, CNRS UMR 5165, Toulouse, France Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Offer
authors.affiliation: Immunogenomics and inflammation research unit EA 4130, University of Lyon 1, Hôpital Edouard Herriot, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Miossec
authors.affiliation: CNRS Unité 9021, Laboratory of Immunology and Therapeutical chemistry, Institut de Biologie Moléculaire et Cellulaire, Federative Research Center 1589, Strasbourg, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pasquali
authors.affiliation: Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, INSERM Unité Mixte de Recherche 1056, Toulouse, France Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, CNRS UMR 5165, Toulouse, France Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Sebbag
authors.affiliation: Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, INSERM Unité Mixte de Recherche 1056, Toulouse, France Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, CNRS UMR 5165, Toulouse, France Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France Laboratory of Cell Biology and Cytology, Centre Hospitalier Universitaire (CHU) de Toulouse, Institut Fédératif de Biologie, Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism*; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010456:Peptides, Cyclic / Q000276:immunology*; D012217:Rheumatoid Factor / Q000378:metabolism* / Q000494:pharmacology; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000936:Antigen-Antibody Complex; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor
keywords: Ant-CCP; Rheumatoid Arthritis; Rheumatoid Factor; Synovitis; TNF-alpha