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IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies
  1. Lætitia Laurent1,2,3,
  2. Florence Anquetil1,2,3,4,
  3. Cyril Clavel1,2,3,4,
  4. Ndiémé Ndongo-Thiam5,
  5. Géraldine Offer1,2,3,
  6. Pierre Miossec5,
  7. Jean-Louis Pasquali6,
  8. Mireille Sebbag1,2,3,
  9. Guy Serre1,2,3,4
  1. 1Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, INSERM Unité Mixte de Recherche 1056, Toulouse, France
  2. 2Unité Différenciation Épidermique et Auto-Immunité Rhumatoïde, CNRS UMR 5165, Toulouse, France
  3. 3Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France
  4. 4Laboratory of Cell Biology and Cytology, Centre Hospitalier Universitaire (CHU) de Toulouse, Institut Fédératif de Biologie, Toulouse, France
  5. 5Immunogenomics and inflammation research unit EA 4130, University of Lyon 1, Hôpital Edouard Herriot, Lyon, France
  6. 6CNRS Unité 9021, Laboratory of Immunology and Therapeutical chemistry, Institut de Biologie Moléculaire et Cellulaire, Federative Research Center 1589, Strasbourg, France
  1. Correspondence to Professor Guy Serre, Unité “Différenciation Épidermique et Auto-immunité Rhumatoïde”; UMR 5165 INSERM-CNRS-Université Paul Sabatier, Hôpital Purpan, Place du Dr Baylac, 31059 Toulouse cedex 9, France; guy.serre{at}


Objectives 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.

  • Rheumatoid Arthritis
  • Rheumatoid Factor
  • Ant-CCP
  • Synovitis
  • TNF-alpha

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